CN101990541A

CN101990541A - Fused heteroaryl modulators of glucocorticoid receptor, ap-1, and/or nf-kb activity and use thereof

Info

Publication number: CN101990541A
Application number: CN2009801124206A
Authority: CN
Inventors: 段敬武; 戴维·S·温斯坦; 江斌
Original assignee: Bristol Myers Squibb Co
Current assignee: Bristol Myers Squibb Co
Priority date: 2008-02-07
Filing date: 2009-02-05
Publication date: 2011-03-23
Also published as: US20110002952A1; US8304539B2; WO2009100171A1; JP2011511085A; EP2247597A1

Abstract

Novel non-steroidal compounds are provided which are useful in treating diseases or disorders associated with modulation of the glucocorticoid receptor, AP-1, and/or NF-kappaB activity, including metabolic and inflammatory and immune diseases or disorders, having the structure of formula (I): an enantiomer, diastereomer, or tautomer thereof, or a prodrug ester thereof, or a pharmaceutically-acceptable salt thereof, in which: Z is heterocyclo or heteroaryl; A is a S- to 8- membered carbocyclic ring or a S- to 8-membered heterocyclic ring; B1 and B2 rings are pyridyl rings, wherein the B1 and B2 rings are each fused to the A ring and the B1 ring is optionally substituted by one to three groups which are the same or different and are independently selected from R1, R2, and R4, and the B2 ring is optionally substituted by one to three groups which are the same or different and are independently selected from R5, R7, and R3 J1, J2, and J3 are at each occurrence the same or different and are independently - A1QA2-; Q is a bond, O, S, S(O), or S(O)2; A1 and A2 are the same or different and are at each occurrence independently selected from a bond, C1-3 alkylene, substituted C1-3 alkylene, C2-4 alkenylene, and substituted C2-4 alkenylene, provided that A1 and A2 are chosen so that ring A is a 5- to 8-membered carbocyclic or heterocyclic ring; R1 to R11 are as defined herein.

Description

Condensed heteroaryl conditioning agent of glucocorticoid receptor, AP-1 and/or NF-kB activity and uses thereof

Technical field

The present invention relates to new non-steroidal compounds, it is effective conditioning agent of glucocorticoid receptor, AP-1 and/or NF-kB activity, therefore can be used for treating disease or obstacle, described disease or obstacle comprise metabolic trouble or obstacle and inflammatory diseases or obstacle or immune correlated disease or obstacle.The present invention also provides and has comprised described compound compositions and use described compound and composition to treat the method for these diseases or obstacle and relative disease or obstacle.

Background technology

In the expression of regulating several genes, relate to transcription factor NF-KB and AP-1, in mediation inflammatory and immunne response, relate to described gene.NF-κ B regulates the gene transcription that comprises TNF-α, IL-1, IL-2, IL-6, adhesion molecule (selecting element such as E-) and chemokine (such as Rantes) etc.AP-1 regulates the generation of cytokine TNF-α, IL-1, IL-2 and matrix metalloproteinase.Show that target is very effective in the pharmacotherapy of TNF-α (gene that a kind of its expression not only is subjected to NF-κ B adjusting but also regulated by AP-1) in several human inflammatory disorders (comprising rheumatoid arthritis and crohn).Therefore, NF-κ B and AP-1 play a significant role in the initiation of inflammatory disorder and dysimmunity with in continuing.Referring to Baldwin, A.S., Journal of Clin.Investigation, 107,3 (2001); Firestein, G.S., and Manning, A.M., Arthritis and Rheumatism, 42,609 (1999); And Peltz, G., Curr.Opin.in Biotech.8,467 (1997).

In the upstream of AP-1 and NF-κ B multiple signal transduction molecule (kinases and Phosphoric acid esterase) is arranged, these signal transduction molecules (kinases and Phosphoric acid esterase) are potential medicine targets.Kinases JNK brings into play keying action in phosphorylation of regulating c-jun (constituting one of subunit of AP-1 mixture (fos/c-jun)) and activation subsequently.Show that the compound that suppresses JNK is effective in the animal model of inflammatory diseases.Referring to Manning, A.M.and Davis, R.J., Nature Rev.Drug Disc., V.2,554 (2003).Kinases crucial with regard to the activation of NF-κ B is I kappa b kinase (IKK).This kinases plays a significant role in the phosphorylation of I κ B.In case I κ B is by phosphorylation, it just experiences degraded, and this causes the release of NF-κ B, and described NF-κ B can be transferred in the nuclear and activate transcribing of said gene.Show that the IKK inhibitor is that BMS-345541 is effective in the animal model of inflammatory diseases.Referring to Burke, J.R., Curr.Opin.Drug Discov.Devel., Sep; 6 (5), 720-8, (2003).

Show that the signal transduction cascade that relates to (signaling cascade), glucocorticoid receptor also interacts by direct physics and suppresses the activity of NF-κ B and AP-1 in the activation that is suppressed at NF-κ B and AP-1.Glucocorticoid receptor (GR) is the member of transcription factor nuclear hormone receptor family and the member of transcription factor steroid hormone family.The proteic affinity labelling of glucocorticoid receptor (affinity labeling) allows the generation of antireceptor antibody, and this has promoted the clone of glucocorticoid receptor.Result in the mankind is referring to Weinberger et al., Science, 228,740-742 (1985) and Weinberger et al., Nature, 318,670-672 (1986), and the result in rat is referring to Miesfeld, R., Nature, 312,779-781 (1985).

Used since 50 years with the interactional glucocorticosteroid of GR and treated inflammatory diseases.Clear demonstration, glucocorticosteroid is brought into play its anti-inflammatory activity by GR to the inhibition of transcription factor NF-KB and AP-1.This inhibition is called as trans-repression (transrepression).Show that the dominant mechanism that GR suppresses these transcription factors is to interact by direct physics.This interaction changes transcription factor complex and suppresses NF-κ B and AP-1 stimulates the ability transcribe.Referring to Jonat, C.et al., Cell, 62,1189 (1990); Yang-Yen, H.F.et al., Cell, 62,1205 (1990); Diamond, M.I.et al., Science 249,1266 (1990); And Caldenhoven, E.et al., Mol.Endocrinol., 9,401 (1995).Also proposed other mechanism, auxilliary activator (co-activator) has been carried out chelating such as GR.Referring to Kamei, Y.et al., Cell, 85,403 (1996) and Chakravarti, D.et al., Nature, 383,99 (1996).

Except causing trans-repression, the interaction of glucocorticosteroid and GR can also make GR induce some gene transcription.This inducing of transcribing is called as trans-activation (transactivation).Trans-activation needs the dimerization of GR and replys assembly (glucocorticoid responseelement, combination GRE) with glucocorticosteroid.

Recently use can not show in conjunction with the research of the transgenosis GR dimerization deficient mice of DNA, and the trans-activation of GR (DNA in conjunction with) activity can be separated with the trans-repression of GR (non-DNA in conjunction with) effect.These researchs also show, the multiple side effect of glucocorticoid therapy is because GR can induce transcribing of the several genes that relates in metabolism, and do not need DNA bonded trans-repression to cause inhibition to inflammation.Referring to Reichardt, H.M.et al., Cell, 93,531 (1998) and Reichardt, H.M., EMBO J., 20,7168 (2001).

The compound of regulating AP-1 and NF-kB activity can be used for treating inflammatory diseases and obstacle and Immunological diseases and obstacle, such as osteoarthritis, rheumatoid arthritis, multiple sclerosis, asthma, inflammatory bowel, transplant rejection and graft versus host disease (GVH disease).

In addition,, be known that glucocorticosteroid is potent anti-inflammatory agent, yet the use of their systematicness is subject to side effect for the glucocorticoid receptor approach.It should be very useful for the numerous patients that suffer from inflammatory diseases that reservation glucocorticosteroid anti-inflammatory usefulness makes the minimized compound of side effect (such as diabetes, osteoporosis and glaucoma) simultaneously.

In addition, about GR, this area need be carried out the compound of antagonism to trans-activation.Described compound can be used for treating and the relevant metabolic trouble of glucocorticosteroid level raising, such as diabetes, osteoporosis and glaucoma.

In addition, about GR, this area need cause the compound of trans-activation.Described compound can be used for treating and the not enough relevant metabolic trouble of glucocorticosteroid.Described disease comprises Addison disease (Addison ' s disease).

Summary of the invention

The present invention relates to new non-steroidal compounds, it is effective conditioning agent of glucocorticoid receptor, AP-1 and/or NF-kB activity, therefore can be used for treating disease or obstacle, described disease or obstacle comprise metabolic trouble or obstacle and inflammatory diseases or obstacle or immune correlated disease or obstacle.The present invention also provides and has comprised described compound compositions and described combination of compounds and use described compound, combination and composition to treat the method for these diseases or obstacle and relative disease or obstacle.

One aspect of the invention (embodiment 1) provides compound or its enantiomer, diastereomer, tautomer or the pharmacologically acceptable salt with formula I structure:

Wherein

Z is selected from heterocyclic radical, heteroaryl and cyano group;

A is selected from 5 to 8 yuan of carbocyclic rings and 5 to 8 yuan of heterocycles;

B ₁And B ₂Ring is pyridyl ring, wherein B ₁And B ₂Ring condenses with the A ring separately, and B ₁Ring is optional to be replaced by one to three group, and described group is identical or different and independently be selected from R ₁, R ₂And R ₄, and B ₂Ring is optional to be replaced by one to three group, and described group is identical or different and independently be selected from R ₅, R ₇And R ₈

J ₁, J ₂And J ₃Identical or different and when occurring, independently be-A at every turn ₁QA ₂-;

Q independently is selected from chemical bond, O, S, S (O) and S (O) at every turn when occurring ₂

A ₁And A ₂Identical or different and when occurring, independently be selected from chemical bond, C at every turn _1-3The C of alkylidene group, replacement _1-3Alkylidene group, C _2-4The C of alkenylene and replacement _2-4Alkenylene, condition are to select A ₁And A ₂So that ring A is 5 to 8 yuan of carbocyclic rings or 5 to 8 yuan of heterocycles;

R ₁, R ₂, R ₄, R ₅, R ₇And R ₈Identical or different and when occurring, independently be selected from alkyl, thiazolinyl, the thiazolinyl of replacement, alkynyl, the alkynyl of replacement, alkoxyl group, the alkoxyl group of replacement, nitro, cyano group, the OR of (i) hydrogen, halogen, alkyl, replacement at every turn ₁₂,-NR ₁₂R ₁₃,-C (=O) R ₁₂,-CO ₂R ₁₂,-C (=O) NR ₁₂R ₁₃,-OC (=O) NR ₁₂R ₁₃,

,-OC (=O) R ₁₂,-NR ₁₂C (=O) R ₁₃,-NR ₁₂C (O) OR ₁₃,-NR ₁₂C (S) OR ₁₃,-S (O) _pR ₁₆, NR ₁₂SO ₂R ₁₆, dialkyl amido alkoxyl group, alkoxyalkyl oxygen base alkyl oxy, SO ₂NR ₁₂R ₁₃, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, heterocyclic radical, aryl and heteroaryl; And/or (ii) when feasible, R ₁, R ₂, R ₄, R ₅, R ₇And R ₈In each and be positioned at R on the adjacent atom ₁, R ₂, R ₄, R ₅, R ₇And R ₈In any form condensed ring with the atom that they connected;

R ₉And R ₁₀Identical or different and when occurring, independently be selected from alkyl, thiazolinyl, the thiazolinyl of replacement, alkynyl, the alkynyl of replacement, nitro, cyano group, the OR of (i) hydrogen, halogen, alkyl, replacement at every turn ₁₄, NR ₁₄R ₁₅, C (=O) R ₁₄, CO ₂R ₁₄, C (=O) NR ₁₄R ₁₅,-O-C (=O) R ₁₄, NR ₁₄C (=O) R ₁₅, NR ₁₄C (=O) OR ₁₅, NR ₁₄C (=S) OR ₁₅, S (O) _pR ₁₇, NR ₁₄SO ₂R ₁₇, SO ₂NR ₁₄R ₁₅, cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl and heteroaryl; Or (ii) R ₉And R ₁₀Form thiazolinyl, cycloalkyl, cycloalkenyl group or the heterocyclic radical of carbonyl, thiazolinyl, replacement with the atom that they connected;

R ₁₁When occurring, independently be selected from alkyl, aryl, heteroaryl, heterocyclic radical and the cycloalkyl of hydrogen, alkyl, replacement at every turn;

R ₁₂, R ₁₃, R ₁₄And R ₁₅Identical or different and when occurring, independently be selected from thiazolinyl, the alkynyl of alkyl, thiazolinyl, the replacement of (i) hydrogen, alkyl, replacement, alkynyl, cycloalkyl, cycloalkenyl group, aryl, heteroaryl and the heterocyclic radical of replacement at every turn; Or (ii) when feasible, R ₁₂With R ₁₃Form heteroaryl ring or heterocyclic ring together, and/or when feasible, R ₁₄With R ₁₅Form heteroaryl ring or heterocyclic ring together;

R ₁₆And R ₁₇Identical or different and when occurring, independently be selected from thiazolinyl, the alkynyl of alkyl, thiazolinyl, the replacement of alkyl, replacement, alkynyl, cycloalkyl, cycloalkenyl group, aryl, heteroaryl and the heterocyclic radical of replacement at every turn; With

P is 0,1 or 2.

Other embodiment of the present invention is as described below.

Embodiment 2: as compound or its enantiomer, diastereomer, tautomer or the pharmacologically acceptable salt of definition in embodiment 1, wherein

J ₁Be chemical bond, O, S, SO, SO ₂, CH ₂Or CH ₂CH ₂(J wherein particularly ₁Be O, S, SO or SO ₂Compound, J wherein more especially ₁Compound for O); With

J ₂And J ₃The chemical bond of respectively doing for oneself.

Embodiment 3: as compound or its enantiomer, diastereomer, tautomer or the pharmacologically acceptable salt that in embodiment 1-2, defines, wherein three loop sections

For

And particularly wherein For

Compound.

Embodiment 4: as compound or its enantiomer, diastereomer, tautomer or pharmacologically acceptable salt, the wherein R that in embodiment 1-3, defines ₁, R ₂, R ₇And R ₈The hydrogen of respectively doing for oneself.

Embodiment 5: as compound or its enantiomer, diastereomer, tautomer or pharmacologically acceptable salt, the wherein R that in embodiment 1-4, defines ₄Be selected from alkyl sulfenyl, aryl, the aryl of replacement, cyano group, the CF of hydrogen, alkyl, thiazolinyl, alkyl sulfenyl, replacement ₃, alkoxyl group, halogen, hydroxyl, dialkyl amido, alkyl monosubstituted amino, dialkyl amido alkoxyl group, alkoxyl group alkoxyl group alkoxyl group and have one to three heteroatomic 4 to 7 yuan of heterocyclic radical that are selected from O, S and N.Preferred compound is such compound, wherein R ₄Be hydrogen, C _1-6Alkyl, halogen, cyano group ,-SC _1-6Alkyl, C _2-6Thiazolinyl, replacement or unsubstituted phenyl, (C _1-6Alkyl) _1-2Amino and have one to three heteroatomic 5 to 6 yuan of heterocyclic radical that are selected from O, S and N.Particularly preferred compound is such compound, wherein R ₄Be hydrogen, methyl, chlorine, sec.-propyl sulfenyl, vinyl, phenyl, cyano group, dimethylamino, N-pyrrolidyl or N-morpholinyl.

Embodiment 6: as compound or its enantiomer, diastereomer, tautomer or pharmacologically acceptable salt, the wherein R that in embodiment 1-5, defines ₅Be selected from hydrogen, haloalkyl, alkoxyl group, halogenated alkoxy, halogen, amino, dialkyl amido, heterocyclic radical, phenyl, halogenophenyl, alkyl (halo) _0-1Aryl, heterocyclic radical carbonyl (halo) _0-1Aryl, alkoxyl group (halo) _0-1Aryl, carboxyl (halo) _0-1Aryl, alkyl amino-carbonyl (halo) _0-1Aryl, dialkyl amino carbonyl (halo) _0-1Aryl, alkylamino, hydroxyl, dialkyl amido alkoxyl group, aryl-alkyl amino, alkoxy aryl alkylamino, alkyl heterocyclic, arylalkyl, heterocyclic radical alkoxyl group, aryl-heterocyclic base, arylalkyl (alkyl) amino, halogenated aryl, dialkyl amido (halo) _0-1Aryl, alkoxyl group alkoxyl group alkoxyl group, alkyl-carbonyl-amino, heteroaryl, dialkyl group (halo) _0-1Aryl, alkyl (halo) _0-1Aryl, hydroxyl (halo) _0-1Aryl, alkoxy carbonyl (halo) _0-1Aryl, alkyl-carbonyl-amino (halo) _0-1Aryl, dialkyl amino sulfonyl (halo) _0-1Aryl, alkyl sulfonyl-amino (halo) _0-1Aryl, alkyl sulfenyl (halo) _0-1Aryl, amino (halo) _0-1Aryl, alkyl-carbonyl aryl, alkyl-carbonyl (halo) aryl, aryloxy (halo) _0-1Aryl, alkyl sulphonyl aryl, alkyl sulphinyl aryl, mercapto oxygen Ji Fangji (thioxyaryl), cycloalkyloxy aryl, cycloalkyl amino carbonyl and cyano group (halo) _0-1Aryl.Preferred compound is such compound, wherein R ₅Be halogen, (C _1-6) _1-2Alkylamino, morpholinyl carbonyl (halo) _0-1Phenyl, (halo) _0-2Pyrrolidyl carbonyl (halo) _0-1Phenyl, ethylenimine base carbonyl (halo) _0-1Phenyl, C _1-6Alkyl-carbonyl (halo) _0-1Phenyl, phenoxy group (halo) _0-1Phenyl, C _1-6Alkoxyl group (halo) _0-1Phenyl, trifluoromethoxy (halo) _0-1Phenyl, (C _1-6) _1-2Alkyl amino sulfonyl (halo) _0-1Phenyl, alkyl sulfenyl (halo) _0-1Phenyl, C _1-6Alkyl sulphinyl (halo) _0-1Phenyl and C _1-6Alkyl sulphonyl (halo) _0-1Phenyl particularly preferably is following compound, wherein

R ₅For chlorine, dimethylamino,

X _aBe hydrogen or fluorine; With

X _bBe selected from (methyl) ₂NC (O)-,

(ethyl) (methyl) NC (O)-,

Methyl C (O)-,-O (phenyl) ,-OCF ₃,-SO ₂N (methyl) ₂, (tertiary butyl) NHC (O)-,-S (sec.-propyl) ,-S (methyl) ,-O (sec.-propyl) ,-S (O) (methyl) ,-S (O) ₂(methyl),

S (O) (sec.-propyl), S (O) ₂(sec.-propyl), S (O) (ethyl), isobutyl-,-O (tertiary butyl) ,-S (ethyl), isobutyl-, sec.-propyl ,-O (cyclopentyl), ethyl C (O)-,

With-C (O) N (methyl) (cyclopropyl).

Embodiment 7: as compound or its enantiomer, diastereomer, tautomer or the pharmacologically acceptable salt that in embodiment 1-6, defines, wherein

For

Or

Wherein

R ₄Be hydrogen, methyl, chlorine, sec.-propyl sulfenyl, vinyl, phenyl, cyano group, dimethylamino, N-pyrrolidyl or N-morpholinyl; With

R ₅For chlorine, dimethylamino,

X _aBe hydrogen or fluorine; With

X _bBe selected from (methyl) ₂NC (O)-,

(ethyl) (methyl) NC (O)-,

With-C (O) N (methyl) (cyclopropyl).

Embodiment 8: as compound or its enantiomer, diastereomer, tautomer or the pharmacologically acceptable salt that in embodiment 1-7, defines, wherein

R ₉And R ₁₀(i) identical or different and independently be selected from the alkyl of hydrogen, alkyl and replacement; Or (ii) R ₉And R ₁₀Form C with the atom that they connected _3-6Cycloalkyl; With

R ₁₁Be hydrogen.

Embodiment 9: as compound or its enantiomer, diastereomer, tautomer or pharmacologically acceptable salt, the wherein R that in embodiment 1-8, defines ₉And R ₁₀Independently be selected from methyl separately, or R ₉And R ₁₀Form cyclopropyl, cyclobutyl or cyclopentyl with the carbon that they connected, and R wherein particularly ₉And R ₁₀The methyl of respectively doing for oneself.

Embodiment 10: as compound or its enantiomer, diastereomer, tautomer or the pharmacologically acceptable salt that in embodiment 1-9, defines, wherein

Z is 5 to 6 yuan of heteroaryls or 5 to 6 yuan of heterocyclic radicals, and described group is substituted with R separately ^m, R ⁿAnd/or R ^oIn one, two or three group, described R ^m, R ⁿAnd/or R ^oIdentical or different and independently be selected from alkyl, thiazolinyl, the thiazolinyl of replacement, alkynyl, the alkynyl of replacement, nitro, cyano group, the OR of hydrogen, halogen, alkyl, replacement ^c, NR ^aR ^b, C (=O) R ^a, CO ₂R ^a, C (=O) NR ^aR ^b,-O-C (=O) R ^a, NR ^aC (=O) R ^b, NR ^aC (=O) OR ^b, NR ^aC (=S) OR ^b, S (O) _pR ^c, NR ^aSO ₂R ^c, SO ₂NR ^aR ^b, cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl and heteroaryl, wherein p is 0,1 or 2;

R ^aAnd R ^bIdentical or different and when occurring, independently be selected from thiazolinyl, the alkynyl of alkyl, thiazolinyl, the replacement of (i) hydrogen, alkyl, replacement, alkynyl, cycloalkyl, cycloalkenyl group, aryl, heteroaryl and the heterocyclic radical of replacement at every turn; Or (ii) when feasible, R ^aAnd R ^bForm heteroaryl ring or heterocyclic ring with the atom that they connected; With

R ^cWhen occurring, independently be selected from thiazolinyl, the alkynyl of alkyl, thiazolinyl, the replacement of alkyl, replacement, alkynyl, cycloalkyl, cycloalkenyl group, aryl, heteroaryl and the heterocyclic radical of replacement at every turn.

Embodiment 11: as compound or its enantiomer, diastereomer, tautomer or the pharmacologically acceptable salt that in embodiment 1-10, defines, wherein

Z is

R ^mAnd R ⁿIdentical or different and when occurring, independently be selected from every turn hydrogen ,-CO ₂R ^a,-C (O) NR ^aR ^b, C _1-6Alkyl ,-CF ₃,-CH ₂OH ,-SR ^c,-NR ^aR ^b,-CH ₂F, cyano group and C _3-6Cycloalkyl (particularly following compound, wherein R ^mBe hydrogen; And R ⁿFor hydrogen ,-C (O) NH (cyclopropyl) ,-C (O) NH (methyl) ,-C (O) N (methyl) ₂,-C (O) NH (ethyl), methyl ,-C (O) O (ethyl) ,-C (O) NH (cyclobutyl) or

R ^oBe hydrogen or C _1-6Alkyl;

R ^aAnd R ^b(i) identical or different and when occurring, independently be selected from hydrogen, C at every turn _1-6The C of alkyl, replacement _1-6Alkyl, have heteroatomic 4 to 7 yuan of heterocyclic radicals and C that 1-3 is selected from O, S or N _3-6Cycloalkyl; Or (ii) R ^aWith R ^bForm together and have 1-3 heteroatomic 4 to the 7 yuan of heterocyclic radicals that are selected from O, S or N; And R ^cBe selected from C _1-6Alkyl and C _3-6Cycloalkyl.

Embodiment 12: as compound or its enantiomer, diastereomer, tautomer or the pharmacologically acceptable salt that in embodiment 1-11, defines, wherein

Z is

With

R ⁿFor hydrogen ,-C (O) NH (cyclopropyl) ,-C (O) NH (methyl) ,-C (O) N (methyl) ₂,-C (O) NH (ethyl), methyl ,-C (O) O (ethyl) ,-C (O) NH (cyclobutyl) ,-C (O) NH (CH ₂) ₂OH ,-C (O) NH (sec.-propyl) ,-C (O) NHCH ₂(CF ₃),

Cyclopropyl or

Embodiment 13: as the compound or its enantiomer, diastereomer, tautomer or the pharmacologically acceptable salt that define in embodiment 1-12, described compound has following structure:

Wherein

R ₅For chlorine, dimethylamino,

X _aBe hydrogen or fluorine; With

X _bBe selected from (methyl) ₂NC (O)-, (ethyl) (methyl) NC (O)-,

S (O) (sec.-propyl), S (O) ₂(sec.-propyl), S (O) (ethyl), isobutyl-,-O (tertiary butyl) ,-S (ethyl), isobutyl-, sec.-propyl ,-O (cyclopentyl), ethyl C (O)-, With-C (O) N (methyl) (cyclopropyl).

The present invention can be presented as other specific form and not break away from purport of the present invention or base attribute.The present invention also comprises all combinations of the optional aspect of the described the present invention of the application.It should be understood that any and all embodiments of the present invention all can with any other embodiment combination to describe the extra embodiment of the present invention.And, any key element of embodiment (comprising independent variable-definition) can with any of any embodiment and all other factor combinations to describe extra embodiment.The present invention also provides pharmaceutical composition, and described pharmaceutical composition comprises formula I compound or its enantiomer, diastereomer or pharmacologically acceptable salt and pharmaceutically acceptable carrier.

Other embodiment of the present invention is 1) method of treatment disease or obstacle, described method comprises the formula I compound of the patient treatment significant quantity that needs treatment, 2) be used for the treatment of the formula I compound of disease or obstacle, with 3) formula I compound is used for the treatment of purposes in the medicine of disease or obstacle in preparation, and wherein said disease or obstacle are selected from endocrine regulation, rheumatosis, collagenosis, tetter, allergic disease, ophthalmic diseases, respiratory system disease, hemopathy, gastrointestinal illness, inflammatory diseases, Immunological diseases, neoplastic disease and metabolic trouble.

In another embodiment, the invention provides the method for the following disease of treatment: endocrine regulation, rheumatosis, collagenosis, tetter, allergic disease, ophthalmic diseases, respiratory system disease, hemopathy, gastrointestinal illness, inflammatory diseases, Immunological diseases, neoplastic disease, metabolic trouble, transcribe the relevant disease of expression of gene product that is subjected to glucocorticoid receptor to stimulate or suppress with it, with the disease of transcribing relevant disease by AP-1 and/or NF-κ B inductive or being correlated with the genetic expression that depends on AP-1 and/or NF-κ B, wherein said disease is relevant with the expression of gene under AP-1 and/or NF-κ B (particularly AP-1) regulation and control, comprise inflammatory diseases as described below and obstacle and Immunological diseases and obstacle, described method comprises that the formula I compound of the present invention with the treatment significant quantity gives patient's step.

Other embodiment of the present invention is 1) method of treatment disease or obstacle, described method comprises the formula I compound of the patient treatment significant quantity that needs treatment, 2) be used for the treatment of the formula I compound of disease or obstacle, with 3) formula I compound is used for the treatment of purposes in the medicine of disease or obstacle in preparation, wherein said disease or obstacle are selected from metabolic trouble or inflammatory diseases or Immunological diseases, and described purposes comprises the formula I compound of the patient treatment significant quantity that needs treatment.

The preferred embodiment of the present invention provides 1) method of treatment disease or obstacle, described method comprises the formula I compound of the patient treatment significant quantity that needs treatment, 2) be used for the treatment of the formula I compound of disease or obstacle, with 3) formula I compound is used for the treatment of purposes in the medicine of disease or obstacle in preparation, wherein said disease or obstacle are selected from metabolic trouble, and wherein said metabolic trouble is selected from type i diabetes, type ii diabetes, juvenile diabetes and obesity.

Other embodiment preferred of the present invention is 1) method of treatment disease or obstacle, described method comprises the formula I compound of the patient treatment significant quantity that needs treatment, 2) be used for the treatment of the formula I compound of disease or obstacle, with 3) formula I compound is used for the treatment of purposes in the medicine of disease or obstacle in preparation, and wherein said disease or obstacle are to be selected from following inflammatory diseases or Immunological diseases: kidney, liver, heart, lungs, pancreas, marrow, cornea, small intestine, the skin allograft, the transplant rejection of skin autograft of the same race and heart valve heterograft, serum sickness, graft versus host disease (GVH disease), rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, asthma, inflammatory bowel, crohn, ulcerative colitis, pyoderma gangraenosum, systemic lupus erythematous, myasthenia gravis, psoriasis, dermatitis, dermatomyositis, eczema, seborrheic dermatitis, pneumonia, uveitis, hepatitis, Graves disease, Hashimoto thyroiditis, autoimmune thyroiditis, Bei Qiete or xerodermosteosis, pernicious or immune hemolysis anaemia, atherosclerosis, Addison disease, the hypoadrenalism of the special property sent out, polyadenous systemic autoimmune disease, glomerulonephritis, scleroderma, morphea, lichen planus, vitiligo, alopecia areata, the autoimmunity baldness, the autoimmunity hypopituitarism, Ge-Ba syndrome, pulmonary alveolitis, contact hypersensitivity, delayed type hypersensitivity, contact dermatitis, urticaria, skin allergic reaction, the respiratory system transformation reactions, pollinosis, gluten sensitive enteropathy, osteoarthritis, acute pancreatitis, chronic pancreatitis, adult respiratory distress syndrome, Sezary syndrome, restenosis, narrow, adrenal,congenital hyperplasia, the apyetous thyroiditis, the hypercalcemia relevant with cancer, juvenile rheumatoid arthritis, ankylosing spondylitis, acute and subacute bursitis, acute non-specific tenosynovitis, acute gouty arthritis, osteoarthritis after the wound, synovitis in the osteoarthritis, epicondylitis, acute rheumatic carditis, pemphigus, the epidermolysis dermatitis herpetiformis, the severe erythema multiforme, exfoliative dermatitis, seborrheic dermatitis, seasonal or annual allergic rhinitis, bronchial asthma, atopic dermatitis, drug hypersensitivity, allergic conjunctivitis, keratitis, herpes zoster ophthalmicus, iritis, iridocyclitis, choroidoretinitis, optic neuritis, the illness sarcoidosis, burst or disseminata phthisis chemotherapy, adult's idiopathic thrombocytopenic purpura, adult's secondary thrombocytopenia, acquired (autoimmunity) hemolytic anemia, become human leukemia and lymphoma, the children acute leukemia, regional enteritis, the autoimmunity vasculitis, Sepsis and chronic obstruction tuberculosis.

Particularly preferred embodiment is 1) method of treatment disease or obstacle, described method comprises the formula I compound of the patient treatment significant quantity that needs treatment, 2) be used for the treatment of the formula I compound of disease or obstacle, with 3) formula I compound is used for the treatment of purposes in the medicine of disease or obstacle in preparation, and wherein said disease or obstacle are selected from transplant rejection, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, asthma, inflammatory bowel, systemic lupus erythematous and psoriasis.

Another embodiment of the present invention relates to transcribing the method that the relevant disease of the expression of gene product that stimulated by glucocorticoid receptor or suppress or obstacle are treated with it, or to transcribe the method that relevant disease or obstacle are treated by AP-1 and/or NF-κ B (particularly AP-1) inductive, or the method that the disease relevant with the genetic expression that depends on AP-1 and/or NF-κ B (particularly AP-1) or obstacle are treated, wherein said disease is relevant with the expression of gene under AP-1 and/or NF-κ 3 (particularly AP-1) regulation and control, such as inflammatory disorder and dysimmunity, cancer and tumour obstacle are such as solid tumor, lymphoma and leukemia and fungi infestation are such as mycosis fungoides.

In another embodiment, the invention provides drug regimen, described drug regimen comprises one or more formulas I compound and immunosuppressor, carcinostatic agent, antiviral agent, anti-inflammatory agent, anti-mycotic agent, microbiotic, anti-angiogenic hyper-proliferative agent, antidepressive, the lipid depressant, lipid regulating agent, antidiabetic, antiobesity agent, hypotensive agent, anticoagulant and/or osteoporosis agent, wherein said antidiabetic is a biguanides, sulfonylurea, glucosidase inhibitor, the PPAR gamma agonist, PPAR α/γ dual agonists, the SGLT2 inhibitor, the DP4 inhibitor, the aP2 inhibitor, euglycemic agent, glucagon-like peptide-1 (GLP-1), in Regular Insulin and/or the meglitinide (meglitinide) a kind, 2 kinds, 3 kinds or more kinds of, wherein said antiobesity agent is a 'beta '3 adrenergic agonists, lipase inhibitor, thrombotonin (and Dopamine HCL) reuptake inhibitor, the thryoid receptor agonist, aP2 inhibitor and/or anoretic, wherein said lipid depressant is the MTP inhibitor, HMG CoA reductase inhibitor, inhibitor for squalene synthetic enzyme, fiber acid derivative, adjust on the ldl receptor activity, lipoxidase inhibitor or ACAT inhibitor, wherein said hypotensive agent are ACE inhibitor, angiotensin II receptor antagonists, the NEP/ACE inhibitor, calcium channel blocker and/or beta-adrenergic blocking agent.

Preferred combination is such combination, wherein said antidiabetic is a N1,N1-Dimethylbiguanide, Glyburide, glimepiride, lattice row pyridine, Glipizide, P-607, gliclazide, acarbose, miglitol, pioglitazone, troglitazone, rosiglitazone, Regular Insulin, Gl-262570, isaglitazone, JTT-501, NN-2344, L895645, YM-440, R-119702, AJ9677, repaglinide, nateglinide, KAD1129, AR-HO39242, GW-409544, KRP297, AC2993, LY315902, among P32/98 and/or the NVP-DPP-728A a kind, 2 kinds, 3 kinds or more kinds of, wherein said antiobesity agent is an orlistat, ATL-962, AJ9677, L750355, CP331648, sibutramine, topiramate, axokine, dextroamphetamine, phentermine, Phenylpropanolamine and/or Mazindol, wherein said lipid depressant is general Liprevil, lovastatin, Simvastatin, atorvastatin, Cerivastatin, fluvastatin, itavastatin, visastatin, fenofibrate, gemfibrozil, clofibrate, avasimibe, TS-962, MD-700, Cholestagel, nicotinic acid and/or LY295427, wherein said hypotensive agent is an ACE inhibitor, and it is a captopril, fosinopril, enalapril, lisinopril, quinapril, benazepril, fentiapril, Ramipril or moexipril; The NEP/ACE inhibitor, it is omapatrilat, [S[(R*, R*)]-six hydrogen-6-[(2-sulfydryl-1-oxo-3-phenyl propyl) amino]-2,2-dimethyl-7-oxo-1H-azepine

-1-acetate (gemopatrilat) or CGS 30440;

Angiotensin II receptor antagonists, it is irbesartan, losartan or valsartan;

Amlodipine besylate, PRAZOSINI HYDROCHLORIDE, verapamil, nifedipine, nadolol, Proprasylyte, carvedilol or Tenso-Timelets, wherein said anticoagulant are acetylsalicylic acid, clopidogrel, ticlopidine, Dipyridamole or Ifetroban;

Described immunosuppressor is ciclosporin, mycophenolate, interferon beta, deoxyspergolin, FK-506 or Ant.-IL-2;

Described carcinostatic agent is that azathiprine, 5-fluorouracel, endoxan, cis-platinum, methotrexate, thiophene are for group or carboplatin;

Described antiviral agent is Abacavir, acyclovir, ganciclovir, zidanocin or vidarabine; With

Described anti-inflammatory agent is Ibuprofen BP/EP, celecoxib, rofecoxib, acetylsalicylic acid, Naproxen Base, Ketoprofen, diclofenac sodium, indomethacin, piroxicam, prednisone, dexamethasone, hydrocortisone or Ledercort A.

Term used in this application " disease relevant with the GR trans-activation " is meant transcribes the relevant disease of gene transcription product that is subjected to the GR trans-activation with it.Described disease includes but not limited to osteoporosis, diabetes, glaucoma, flesh loss (muscle loss), facial protuberance (facial swelling), personality change (personality change), hypertension, obesity, dysthymia disorders, AIDS, wound healing illness (conditionof wound healing), primary or secondary hypocortisolism and Addison disease.

The term that is various grammatical forms used in this application " treatment (treat) ", " treatment (treating) " or " treatment (treatment) " be meant prevention, reduce or alleviate, partially or completely improvement or cure diseases, obstacle or illness, and wherein prevention represents to suffer from described disease to being in, the people in obstacle or the illness danger treat.

Term used in this application " glucocorticoid receptor " and " GR " are meant in conjunction with glucocorticosteroid and stimulate or the member or the GR-β of transcription factor nuclear hormone receptor (" the NHR ") family that suppresses to transcribe.

These terms used in this application are meant the glucocorticoid receptor from any source, include but not limited to the human glucocorticoid receptor, as Weinberger et al., Science, 228:740-742 (1985) and Weinberger et al., Nature is disclosed in the 318:670-672 (1986); The rat glucocorticoid receptor, as Miesfeld R., Nature is disclosed in the 312:779-781 (1985); The mouse glucocorticoid receptor, as Danielson, M.et al., EMBO J. is disclosed in the 5:2513; The sheep glucocorticoid receptor, as Yang, K.et al., J.Mol.Endocrinol. is disclosed in the 8:173-180 (1992); The marmoset glucocorticoid receptor, as Brandon, D.D.et al. is disclosed in the J.Mol.Endocrinol.7:89-96 (1991); With people GR-β, as Hollenberg, S.M.et al., Nature, 318:635 (1985) and Bamberger, C.M.et al., J.Clin Invest. is disclosed in the 95:2435 (1995).

Term used in this application " disease or the obstacle relevant with AP-1 and/or NF-κ B " is meant and the expression product relevant disease of gene under AP-1 and/or NF-κ B regulation and control.Such disease includes but not limited to inflammatory diseases and obstacle and Immunological diseases and obstacle; Cancer and tumour obstacle are such as solid tumor, lymphoma and leukemia; And fungi infestation, such as mycosis fungoides.

Term used in this application " inflammatory diseases or obstacle or immune correlated disease or obstacle " comprises having any illness, disease or the obstacle that inflammatory is formed or immunity is formed, and includes but not limited to every kind in the following illness: transplant rejection (for example kidney, liver, heart, lungs, pancreas (for example islet cells), marrow, cornea, small intestine, skin allograft, skin autograft of the same race (such as being used for burn treatment) and heart valve heterograft), serum sickness and graft versus host disease (GVH disease); Autoimmune disorder is such as rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, I type and type ii diabetes, juvenile diabetes, obesity, asthma, inflammatory bowel (such as crohn and ulcerative colitis), pyoderma gangraenosum, lupus (systemic lupus erythematous), myasthenia gravis, psoriasis, dermatitis, dermatomyositis, eczema, seborrheic dermatitis, pneumonia, uveitis, hepatitis, Graves disease, Hashimoto thyroiditis, autoimmune thyroiditis, Bei Qiete or xerodermosteosis (a dried/mouth is done), pernicious or immune hemolysis anaemia, atherosclerosis, Addison disease (suprarenal gland autoimmune disorder), the hypoadrenalism of the special property sent out, polyadenous systemic autoimmune disease (being also referred to as polyadenous systemic autoimmune syndrome), glomerulonephritis, scleroderma, morphea, lichen planus, vitiligo (skin pigment takes off mistake), alopecia areata, the autoimmunity baldness, the autoimmunity hypopituitarism, Ge-Ba syndrome and pulmonary alveolitis; By the cell-mediated hypersensitivity disease of T, comprise contact hypersensitivity, delayed type hypersensitivity, contact dermatitis (comprising the contact dermatitis that causes by toxicodendron), urticaria, skin allergic reaction, respiratory system transformation reactions (pollinosis, rhinallergosis) and gluten sensitive enteropathy (celiac disease); Inflammatory diseases is such as osteoarthritis, acute pancreatitis, chronic pancreatitis, adult respiratory distress syndrome, Sezary syndrome with have vascular disease such as restenosis, the narrow and atherosclerosis that inflammatory is formed and/or proliferative is formed.Inflammatory diseases or obstacle or immune correlated disease or obstacle also include but not limited to endocrine regulation, rheumatosis, collagenosis, tetter, allergic disease, ophthalmic diseases, respiratory system disease, hemopathy, gastrointestinal illness, inflammatory diseases, autoimmune disorder, adrenal,congenital hyperplasia, the apyetous thyroiditis, the hypercalcemia relevant with cancer, juvenile rheumatoid arthritis, ankylosing spondylitis, acute and subacute bursitis, acute non-specific tenosynovitis, acute gouty arthritis, osteoarthritis after the wound, synovitis in the osteoarthritis, epicondylitis, acute rheumatic carditis, pemphigus, the epidermolysis dermatitis herpetiformis, the severe erythema multiforme, exfoliative dermatitis, seborrheic dermatitis, seasonal or annual allergic rhinitis, bronchial asthma, contact dermatitis, atopic dermatitis, drug hypersensitivity, allergic conjunctivitis, keratitis, herpes zoster ophthalmicus, iritis and iridocyclitis, choroidoretinitis, optic neuritis, the illness sarcoidosis, burst or disseminata phthisis.

Synthetic

The preparation method

The compounds of this invention can synthesize by organic chemistry filed several different methods known to the skilled.Therefore, following synthetic schemes only comes the example explanation as the additional method of preparation The compounds of this invention, and it will be conspicuous to those skilled in the art.Similarly, will be it is evident that to those skilled in the art, each step in the synthetic schemes can be undertaken to obtain needed one or more compounds by the alternative order.The embodiment compound is usually according to the form preparation of synthetic schemes 1-6 with racemic mixture.The compound of chiral purity can prepare by technology well known by persons skilled in the art, for example by chirality mutually preparation property HPLC racemic product is separated.The compound of enantiomer enrichment can prepare by known method, and these methods include but not limited to the auxiliary functional group of chirality is incorporated in the racemic intermediate to obtain being enriched with the product of enantiomer after the fracture of the auxiliary functional group of chirality.

Scheme 1 shows by intermediate carboxylic acid 2 preparation title compounds of the present invention (1).Acid amides 1 (1a and 1b) can be prepared by a number of procedures by 2, and described method comprises the dehydrating condensation of carboxylic acid and amine.For example, acid 2 and amine 3 (NHR ₁₁Z, wherein R ₁₁=H, alkyl, cycloalkyl, alkoxyl group, dialkyl amido, aryl or heteroaryl) condensation can followingly carry out: 2 usefulness activators (such as water-soluble carbodiimide (EDC)) are handled, its condition is in the presence of N-hydroxyl triazole (HOAt or HOBt etc.) and amine, in the presence of alkali (preferably triethylamine, diisopropyl ethyl amine etc.), in suitable polar aprotic solvent (N, dinethylformamide, acetonitrile, methylene dichloride etc.).Also can be by handling carboxylic acid 2 and carboxylic acid 2 is converted into acyl chlorides with suitable chlorizating agent (thionyl chloride, oxalyl chloride etc.).Similarly, after being exposed to fluorizating agent (such as cyanuric fluoride), can be converted into acyl fluorides with 2 with 2.Make carboxylic acid halides (acyl chlorides or acyl fluorides) and amine 3 condensations (carrying out in non-protonic solvent in the presence of alkali (such as pyridine or triethylamine) usually) then, this can obtain acid amides 1.At R ₁₁=H (is 3=NH ₂Z) under the situation, 2 and 3 condensation product (1a, R ₁₁=H) can followingly be converted into 1b (R ₁₁=alkyl): in the presence of alkali (cesium carbonate, sodium hydride etc.), handle 1a with alkylating agent (alkyl halide, alkyl sulfonic ester etc.).Selectively, 1a (R ₁₁=H) can followingly be converted into 1b (R ₁₁=C (O) alkyl or CO ₂Alkyl): handle 1a with highly basic (sodium hydride, lithium diisopropylamine etc.), then carry out acylations with suitable acylating agent (acyl chlorides, chloro-formic ester etc.).Similarly, sulfonylation can be realized to obtain 1b (R by handling with alkali and sulfonic acid halide ₁₁=SO ₂Aryl or SO ₂Alkyl).1a is carried out arylation to obtain 1b (R ₁₁=aryl), this also can followingly carry out: acid amides is carried out the catalytic N-arylation of palladium (referring to for example Yin, J.; Buchwald S.Org.Lett.2000,2,1101-1104 and the reference wherein quoted) or make acid amides and aryl boric acid or aryl siloxanes carry out the promoted arylation of copper (referring to for example Lam, P.et al.Synlett 2000,674-676).

Scheme 1

Carboxylic acid 2 and amine 3 condensations are to form product 1

Scheme 2 shows the whole bag of tricks of preparation intermediate carboxylic acid 2.Intermediate ketone 4 can followingly be reduced to alcohol 5: with reductive agent (being generally metal hydride such as sodium borohydride/methyl alcohol or lithium aluminium hydride/ether or THF) intermediate ketone 4 is handled.In a kind of preparation mode, can make above-mentioned alcohol and propanedioic acid condensation after the intermediate dicarboxylic acid of inferring is carried out decarboxylation, to obtain needed intermediate 2 (Jones etal.J.Am.Chem.Soc.1948,70,2843 and Beylin et al.Tetrahedron Lett.1993,34,953-956).Contract silanol (silyl ketene acetal) 6 of alcohol 5 also available ketene is handled.Selectively, alcohol 5 can be in the presence of suitable alkali (triethylamine, pyridine or DMAP) carries out acylations obtaining 5a with acid anhydrides or carboxylic acid halides, and described 5a also can react with the ketene silanol 6 that contracts.At R ₉=R ₁₀=R ₅₀=R ₅₁Under the situation of=Me, 6 are available commercially.Make 5 (J ₂=J ₃=chemical bond) with 6 condensations to obtain ester 7, this needs the existence of Lewis acid (Lewis acid) (such as boron trifluoride diethyl etherate compound (borontrifluoride etherate), titanium tetrachloride etc.) and is preferably in the polar aprotic solvent (such as methylene dichloride) to carry out usually.Ester 7 is carried out saponification to obtain 2, and this available hydrogen sodium oxide or potassium hydroxide carry out in the presence of cosolvent (such as methyl alcohol, THF and/or DMSO) in water.At R ₉=R ₁₀Under the situation of=alkyl, to the hydrolysis of ester 7 be preferably in high temperature (being generally 80 ℃) carry out for a long time (＞5h).

Also can make ketone 4 and come from ester 9 (R ₅₁=alkyl) enolate (enolate) condensation is to obtain ester 10, and described enolate is prepared as follows: handle 9 at low temperature (78 ℃ to ℃) with suitable alkali (lithium diisopropylamine, hexamethyl dimethyl silanyl Lithamide or hexamethyl dimethyl silanyl potassium amide etc.).Intermediate carboxylic acid 10 (R ₅₁=H) also can be prepared as follows: at first use at least two normal highly basic (preferably lithium diisopropylamine or diethylamino lithium) to carboxylic acid 9 (R ₅₁=H) handle to obtain enediol salt dianion (enediolate dianion).The generation of enediol salt is preferably carried out at 0 ℃ to 55 ℃.Make the enediol salt and ketone 4 condensations of preparation in position then, this can obtain alcohol acid 10 (R ₅₁=H).At J ₂And/or J ₃One of for alkylidene group or both are under the situation of alkylidene group, can easily dewater to obtain unsaturated intermediate 11 and/or 12 to intermediate ethanol 10.Dehydration can following spontaneous generation: with 10 (J ₂And J ₃=alkylidene group) is exposed to acidic conditions (such as aqueous acids or Lewis acid (boron trifluoride, titanium tetrachloride etc.)).Intermediate alkene 11 and 12 can reduce to obtain ester 7 (R by catalytic hydrogenation (being generally the palladium/carbon in the presence of hydrogen) ₅₁=alkyl), described ester 7 (R ₅₁=alkyl) can carry out saponification as mentioned above with preparation carboxylic acid 2.Selectively, be carboxylic acid (R at alkene 11 and 12 ₅₁Under=H) the situation, catalytic hydrogenation (being generally the palladium/carbon in the presence of hydrogen) can directly obtain carboxylic acid 2.Can not spontaneous dehydration be under 11 and/or 12 the situation at alcohol 10, can be with 10 (R ₅₁=H) be reduced to 2.Described reduction can followingly be carried out: in the presence of protonic acid (being generally trifluoroacetic acid) with silicomethane (being generally triethyl-silicane) to acid 10 (R ₅₁=H) handle.Also can be converted under the 2 identical conditions ester 10 (R 10 ₅₁=alkyl) is reduced to ester 7.Can under these conditions ester 7 be hydrolyzed to acid 2.

The also available ketene of ketone 4 contracts silanol 6 processing to obtain hydroxy ester 10 (R ₅₁=alkyl).Condensation is preferably in Lewis acid (boron trifluoride diethyl etherate compound etc.) existence and carries out at 0 ℃ in methylene dichloride down.Can separate hydroxy ester 10, or selectively, can in position hydroxy ester 10 be reduced to ester 7.At R ₁, R ₂And R ₄In any or a plurality of be under the situation of OH, in the reaction mixture that contains unsegregated hydroxy ester 10, to add triethyl-silicane, this can obtain ester 7.Selectively, add strong protonic acid (being generally trifluoroacetic acid) and triethyl-silicane in the reaction mixture that contains unsegregated hydroxy ester 10, this can obtain ester 7.Can as mentioned above ester 7 be converted into carboxylic acid 2 then.

Scheme 2

By ketone 3 preparation carboxylic acids 2

Scheme 3 shows the method for preparing intermediate ketone 4.In a kind of approach, 2-chloropyridine 14 can use highly basic (such as lithium diisopropylamine (LDA)) in solvent (such as tetrahydrofuran (THF)) low temperature (78 ℃) handle with regioselectivity ground produce the 3-lithiumation pyridine (Trecourt et al.J.Chem.Soc.PerkinTrans.I 1990,2409-2415).Pyridyl lithium intermediate can react to obtain alcohol 15 through the pyridylaldehyde 13 that chlorine replaces with the ortho position by nucleophilic addition in position.Be oxidized to ketone 16 with 15 under can known in the literature various conditions, such as high idodine of Dai Si-Martin (Dess-Martin Periodinane) or Si Weien (Swern) oxidation in methylene dichloride, carried out.Halogen in 16 can use such as sodium methylate/such condition of backflow methyl alcohol and replace with methoxyl group.Gained dimethoxy derivative 17 when when high temperature is handled with pyridine hydrochloride, can experience cyclisation with obtain diaza folder oxygen anthrone (diazaxanthone) 4a (Trecourt et al.J.Chem.Soc.Perkin Trans.I 1990,2409-2415).In selectable approach, 2-methoxypyridine or 2,6-dimethoxy-pyridine (19, Z=H or OMe) available highly basic is (such as 2,4,6-trimethylphenyl lithium) in tetrahydrofuran (THF), handle with 3 deprotonation (Cominsand LaMunyon, Tetrahedron Lett.1988 that realize regioselectivity at pyridine, 29,773-776).Add aldehyde 18 in the lithiumation pyridine that generates in position, this can obtain alcohol 20.Alcohol 20 also can be following by bromopyridine 21 preparations: carry out lithium-bromine exchange with butyllithium, then be added in the aldehyde 18 (Trecourt et al.J.Chem.Res.1979,46-47).Be converted into ketone 22 with 20, this can use similar oxidizing condition (such as high idodine of Dai Si-Martin or Si Weien oxidation) to realize.Ketone 22 (Z=H or OMe) can be converted into diaza folder oxygen anthrone 4b (Z=H or OMe) according to aforementioned condition.

Show the another kind of method of synthetic diaza folder oxygen anthrone 4c in the bottom of scheme 3.Suitably the pyridine carboxylic acid 23 that replaces can use following condition and be converted into corresponding methyl esters: such as at HCl or H ₂SO ₄Backflow MeOH under existing, the trimethyl silyl diazomethane in tetrahydrofuran (THF) and methyl alcohol or at the methyl iodide in polar solvent (such as DMF or DMSO) in the presence of the alkali (such as salt of wormwood).Ester 24 (Z ₁=OMe) conversion to cyano group ketone 25 can be by making ester 24 (Z ₁=realize with the anionic reactive of acetonitrile that OMe) negatively charged ion of described acetonitrile can produce (referring to for example Ridge, David N.et al, J Med Chem 1979,1385) at solvent in such as THF with LDA.Selectively, cyano group ketone 25 can followingly synthesize: make cyanoacetic acid and butyllithium and acyl chlorides 24 (Z ₁=Cl) in THF, react described acyl chlorides 24 (Z ₁=Cl) can use known condition (such as with thionyl chloride in pyroprocessing or with oxalyl chloride/DMF/CH ₂Cl ₂Handle) and by acid 23 preparations.Vinylogous amide (vinylogous amide) the 27th is available commercially, or can be following by ketone 26 preparations: ketone 26 be used N, dinethylformamide dimethyl acetal (N, N-dimethylformamide dimethyl acetal) is handled, and carries out reflux by the mixture to two kinds of materials usually.The condensation condition of cyano group ketone 25 and vinylogous amide 27 based at the bibliographical information of relevant but different system (Bondavalli et al Synthesis, 1999,1169-1174) develop.Usually, reaction can be carried out to obtain ketone 4c under acidic conditions (being generally acetate) in heat (being generally 100-140 ℃) solvent (being generally DMF or DMA).Then can as in the scheme 2 with regard to 4 to as described in 2 the conversion and further as intermediate 4a-c being processed as described in 1 the conversion with regard to 2 in the scheme 1.

Scheme 3

Scheme 4 shows the synthetic of intermediate ketone 4d.The suitably functionalized pyridine acyl chlorides 24 (it can prepare according to the method described in the scheme 3) and the enolate (it is obtained at low temperature (being generally-78 ℃) in THF by acetone and LDA) of acetone are reacted to obtain diketone 29.To the available N of the conversion of vinylogous amide 30, the dinethylformamide dimethyl acetal is realized at high temperature (being generally reflux temperature) in toluene.Vinylogous amide 30 can use alkali (such as two (trimethyl silyl) Lithamide or LDA) to carry out deprotonation in polar solvent (such as THF).The gained enolate can followingly react to obtain pyrone 32 with acyl chlorides 31: carry out nucleophilic addition, then carry out Michael (Michael) addition reaction/reverse Michael and eliminate reaction.Pyrone can form pyridone and carry out cyclisation to obtain diaza folder oxygen anthrone 4d to induce in pyroprocessing in polar acidic solvent (such as the mixture of acetate and DMF) with ammonia source (such as ammonium acetate).Can as in the scheme 2 with regard to 4 to as described in 2 the conversion and further as intermediate 4d being processed as described in 1 the conversion with regard to 2 in the scheme 1.

Scheme 4

Scheme 5 shows a series of diazas that replace through chlorine and presss from both sides the synthetic of oxygen anthracene and derivatize subsequently.Intermediate 33 can prepare according to the synthetic method described in above scheme 3 and the scheme 2.Oxidation obtains N-oxide intermediate 34, and this can realize being used to prepare under the known conditions of pyridine N-oxides, such as mCPBA (metachloroperbenzoic acid)/methylene dichloride or MeReO ₃And hydrogen peroxide/methylene dichloride (Coperet et al, J.Org.Chem.1998,63,1740).N-oxide intermediate 34 can (be POCl there not being the phosphoryl chloride under the cosolvent situation preferably with suitable chlorizating agent ₃) handle to obtain chlorine diaza folder oxygen anthracene 35.Be hydrolyzed to carboxylic acid 36 with 35, this can realize under just by 2 preparations, 7 described conditions above, preferably under the situation that does not have DMSO.Can just by as described in the 2 and 3 preparation 1a, carboxylic acid 36 be converted into acid amides 37 as above.

Chlorine diaza folder oxygen anthracene 37 usefulness amine (NHR ₁₂R ₁₃) replace at high temperature (being generally 130 ℃), this can obtain 39a.Selectively, 37 can experience cross-coupling reaction by metal mediation to obtain 39b.For example, Su Chuji (Suzuki) coupling can followingly be carried out: 37 usefulness aryl or heteroaryl boric acid or aryl or heteroaryl boric acid ester are handled, its condition is in the presence of palladium catalyst (tetrakis triphenylphosphine palladium etc.) and alkali aqueous solution (salt of wormwood, yellow soda ash, potassiumphosphate etc.), in appropriate solvent or solvent combination (DMF, toluene/ethanol, 1,4-diox etc.) in, high temperature (being generally 100 ℃).Muriate 37 also can experience various cross-coupling reaction well known by persons skilled in the art by the mediation of other metal (referring to for example de Meijere, A. ， ﹠amp; Diederich, F. (2004) .Metal-Catalyzed Cross-Coupling Reactions. (2nd ed): John Wiley ﹠amp; Sons).The also available alkynes of muriate 37 carries out Sonagashira cross-coupling or Stevens-Castro cross-coupling to obtain alkynes 39c, its condition is in the presence of palladium catalyst (preferably two (triphenylphosphine) palladium chloride (II)), use the cuprous iodide of catalytic amount, in the presence of the secondary amine base that is obstructed (preferably diisopropylamine).Muriate 37 also can be converted into nitrile 39d (Sundmeier, M.et al, Eur.J.Inorg.Chem.2003,3513) by the currently known methods that is used for aryl halide is carried out palladium catalysis cyaniding.For example, 37 usefulness cyanide sources (being generally zinc cyanide) are handled, and its condition is in the presence of palladium catalyst (being generally tetrakis triphenylphosphine palladium (0)), in polar solvent (being generally DMF), high temperature (being generally 120 ℃), obtains nitrile 39d thus.Nitrile 39d also can be converted into acid amides 39e in the operation of two steps, described two steps operation relates to by oxyhydroxide (being generally potassium hydroxide) carries out first one-step hydrolysis to obtain carboxylic acid (R ₅=CO ₂H), then as just by 2 the preparation 1a as described in make as described in carboxylic acid (R ₅=CO ₂H) with primary amine or secondary amine condensation to obtain carboxylic acid amides 39e.Also can people (Tetrahedron 2001,57,2507) be described like that muriate 37 is converted into ketone 39f as Jean-Yves Legros etc.Can similarly transform to obtain 38a-f chloro-acid 36, can just described 38a-f be converted into 39a-f according to above by 2 and 3 preparations, 1 described condition.Any racemic intermediate 33-38 or any racemize embodiment compound can be separated into pure single enantiomer by any method known to those skilled in the art.

Scheme 5

Can as described in the scheme 6, further process 2-(phenyl that contraposition is substituted)-diaza folder oxygen anthracene.Phenol 40a (R _x=OH) can under three letter (Mitsunobu) conditions, carry out alkylation (Synthesis 1,1981).Therefore, 40a alcohol (R _yOH) handle, its condition is that in tetrahydrofuran (THF), this can obtain ether 40b in the presence of phosphine (preferably triphenylphosphine) and azodicarboxy acid alkyl ester (preferably diisopropyl azo-2-carboxylic acid or diethylazodicarboxylate).Thioether (41a for example, R _x=SMe) can be by being oxidized to sulfoxide or sulfone 41b with any processing the in the multiple oxygenant, described oxygenant comprises metachloroperbenzoic acid and potassium hydrogen persulfate.Carboxylic acid 42a can use multiple being used for that phenylformic acid is converted into the method for benzamide and is converted into benzamide 42b.Preferably, 42a handles with activator (or multiple activator) (being generally the HOBt in the presence of carbodiimide (such as EDCI)), its condition is in the presence of tertiary amine base (being generally triethylamine or diisopropyl ethyl amine) and primary amine or secondary amine, in polar aprotic solvent (being generally acetonitrile or DMF), obtain benzamide 42b thus.Aldehyde 43a can followingly be converted into pure 43b: aldehyde 43a handles with suitable reductive agent (sodium borohydride etc.) reduction or with organo-metallic nucleophilic reagent (lithium alkylide, lithium aryl, Grignard reagent etc.).Similarly, can make ketone 44a and the condensation of organo-metallic nucleophilic reagent to obtain tertiary alcohol 44b.

Scheme 6

To the 5H-chromene that replaces through phenyl also [2,3-b] pyridine process

Definition

It below is definition to the term that in this specification and the appended claims, uses.Except as otherwise noted, the initial definition that provides for group or term of the application is applicable to this group of occurring at specification sheets and claims or term (separately or as the part of another group) everywhere.

Term " alkyl " is meant the alkyl with 1 to 12 carbon atom (being preferably 1 to 6 carbon atom) of straight or branched.The alkyl that low alkyl group promptly has 1 to 4 carbon atom is most preferred.When numeral marks now below behind the symbol " C ", described subscript has more clearly defined the carbonatoms that concrete group can contain.For example, " C _1-6Alkyl " be meant the alkyl with 1 to 6 carbon atom of straight chain and side chain, such as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, the tertiary butyl, n-pentyl etc.Subscript " 0 " is meant chemical bond.Therefore, term hydroxyl (C _0-2) alkyl or (C _0-2) hydroxyalkyl comprises hydroxyl, hydroxymethyl and hydroxyethyl.

Term " alkyl of replacement " be meant have one, two or three substituent alkyl as defined above, described substituting group be selected from halogen (for example trifluoromethyl), thiazolinyl, replacement thiazolinyl, alkynyl, nitro, cyano group, oxo (=O), OR _a, SR _a, (=S) ,-NR _aR _b,-N (alkyl) ₃ ⁺,-NR _aSO ₂,-NR _aSO ₂R _c,-SO ₂R _c,-SO ₂NR _aR _b,-SO ₂NR _aC (=O) R _b, SO ₃H ,-PO (OH) ₂,-OC (O) R _a,-C (=O) R _a,-CO ₂R _a,-C (=O) NR _aR _b,-C (=O) (C _1-4Alkylidene group) NR _aR _b,-C (=O) NR _a(SO ₂) R _b,-CO ₂(C _1-4Alkylidene group) NR _aR _b,-NR _aC (=O) R _b,-NR _aCO ₂R _b,-NR _a(C _1-4Alkylidene group) CO ₂R _b,=N-OH ,=N-O-alkyl, aryl, cycloalkyl, heterocyclic radical and/or heteroaryl, wherein R _aAnd R _bBe selected from hydrogen, alkyl, thiazolinyl, CO ₂H, CO ₂(alkyl), C _3-7Cycloalkyl, phenyl, benzyl, phenylethyl, naphthyl, 4 to 7 yuan of heterocyclic radicals or 5 to 6 yuan of heteroaryls, or R _aAnd R _bWhen linking to each other, can combine to form heterocyclic radical or heteroaryl, reach R with same nitrogen-atoms _cBe selected from and R _aAnd R _bIdentical group but be not hydrogen.Each R _aAnd R _b(when being not hydrogen) and each R _cChoose wantonly and further have three substituting groups at the most, described substituting group and R _a, R _bAnd/or R _cIn any available carbon atom or nitrogen-atoms link to each other, described substituting group is selected from (C _1-6) alkyl, (C _2-6) thiazolinyl, hydroxyl, halogen, cyano group, nitro ,=O (when valency allows), CF ₃, O (C _1-6Alkyl), OCF ₃, C (=O) H, C (=O) (C _1-6Alkyl), CO ₂H, CO ₂(C _1-6Alkyl), NHCO ₂(C _1-6Alkyl) ,-S (C _1-6Alkyl) ,-NH ₂, NH (C _1-6Alkyl), N (C _1-6Alkyl) ₂, N (CH ₃) ₃ ⁺, SO ₂(C _1-6Alkyl), C (=O) (C _1-4Alkylidene group) NH ₂, C (=O) (C _1-4Alkylidene group) NH (alkyl), C (=O) (C _1-4Alkylidene group) N (C _1-4Alkyl) ₂, C _3-7Cycloalkyl, phenyl, benzyl, phenylethyl, phenyl oxygen base, benzyl oxygen base, naphthyl, 4 to 7 yuan of heterocyclic radicals, 4 to 7 yuan of cycloalkyl or 5 to 6 yuan of heteroaryls.When the alkyl that replaces was substituted with aryl (comprising for example phenyl and naphthyl), heterocyclic radical, cycloalkyl or heteroaryl, described ring system also can have zero, one, two or three substituting groups thus as the definition of following institute, and described substituting group is also as following definition.

It will be understood by those skilled in the art that working as the application uses group " CO ₂" time, this is intended to be meant group

When term " alkyl " used [for example in " arylalkyl "] with another group, this combination had more clearly defined at least one substituting group that alkyl contained that replaces.For example, " arylalkyl " is meant the alkyl that replaces as defined above, and wherein at least one substituting group is an aryl, for example benzyl.Therefore, term aryl (C _0-4) alkyl comprises the low alkyl group of the replacement with at least one aryl substituent, and comprise that also the aryl with another group Direct Bonding [is aryl (C ₀) alkyl].

Term " thiazolinyl " is meant the alkyl with 2 to 12 carbon atoms and at least one two key of straight or branched.Thiazolinyl with 2 to 6 carbon atoms and two keys is most preferred.

Term " alkynyl " is meant the alkyl with 2 to 12 carbon atoms and at least one three key of straight or branched.Alkynyl with 2 to 6 carbon atoms and one three key is most preferred.

Term " alkylidene group " is meant the alkyl with 1 to 12 carbon atom (being preferably 1 to 8 carbon atom) of the straight or branched of divalence, for example { CH ₂- _n, wherein n is 1 to 12, is preferably 1 to 8.The alkylidene group that low-grade alkylidene promptly has 1 to 4 carbon atom is most preferred.Term " alkenylene " and " alkynylene " are meant the divalent group of thiazolinyl and alkynyl as defined above respectively.

When the alkynylene of the alkenylene of the alkylidene group of the alkynyl of the thiazolinyl of mentioning replacement, replacement, replacement, replacement or replacement, these groups are substituted with 1 to 3 defined substituting group of alkyl that as above just replaces.

Term used in this application " inferior assorted alkyl " is meant the alkyl with 2 to 12 carbon atoms (being preferably 2 to 8 carbon atoms) of the straight or branched of saturated and undersaturated divalence, wherein 1 or 2 carbon atom in the straight chain be selected from-O-,-S-,-S (=O)-,-SO ₂-,-NH-and-NHSO ₂-heteroatoms replace.Therefore, term " inferior assorted alkyl " comprise divalence as the alkoxyl group of giving a definition, divalence as the alkylthio of giving a definition and divalence as alkylamino of giving a definition and alkylidene group and the alkenylene that in alkyl chain, has the heteroatoms combination.For example, the application " inferior assorted alkyl " can comprise such as-S-(CH ₂) _1-5NH-CH ₂-,-O-(CH ₂) _1-5S (=O)-CH ₂-,-NHSO ₂-CH ₂-,-CH ₂The group that-NH-etc. are such.Preferably, inferior assorted alkyl do not have two and be selected from adjacent the time-O-and-atom of S-.When subscript is used with the inferior assorted alkyl of term, for example as at C _2-3In the inferior assorted alkyl, described subscript is meant the carbonatoms except that heteroatoms in the group.Therefore, C for example _1-2Inferior assorted alkyl can comprise such as-NH-CH ₂-,-CH ₂-NH-CH ₂-,-CH ₂-CH ₂-NH-,-S-CH ₂-,-CH ₂-S-CH ₂-,-O-CH ₂-NH-CH ₂-,-CH ₂-O-CH ₂-wait such group.

Term " replace inferior assorted alkyl " is meant inferior as defined above assorted alkyl, the nitrogen-atoms in the assorted alkyl chain in its Central Asia or at least one in the carbon atom be not the group bonding (or being substituted with the group that is not hydrogen) of hydrogen.Carbon atom in the inferior assorted alkyl chain can be substituted with and be selected from the top described group of alkyl that just replaces, or further is substituted with the alkyl of alkyl or replacement.Nitrogen-atoms in the inferior assorted alkyl chain can be substituted with and be selected from alkyl, thiazolinyl, alkynyl, cyano group or A ₁-Q-A ₂-R _hGroup, A wherein ₁Be key, C _1-2Alkylidene group or C _2-3Alkenylene; Q be key ,-C (=O)-,-C (=O) NR _d-,-C (=S) NR _d-,-SO ₂-,-SO ₂NR _d-,-CO ₂-or-NR _dCO ₂-; A ₂Be key, C _1-3Alkylidene group, C _2-3Alkenylene ,-C _1-4Alkylidene group-NR _d-,-C _1-4Alkylidene group-NR _dC (=O)-,-C _1-4Alkylidene group-S-,-C _1-4Alkylidene group-SO ₂-or-C _1-4Alkylidene group-O-, wherein said A ₂Alkylidene group be side chain or straight chain and optional be [alkylidene group that just replaces as the application defines] that replaces; R _hAlkyl, thiazolinyl, substituted alkenyl, aryl, heteroaryl, heterocyclic radical or cycloalkyl for hydrogen, alkyl, replacement; And R _dBe selected from the alkyl [as defined in this Application] of hydrogen, alkyl and replacement, yet condition is with regard to the assorted alkyl in the Asia that replaces, and works as A ₁, Q and A ₂When being chemical bond, R _hBe not hydrogen.Work as R _hDuring for aryl, heteroaryl, cycloalkyl or heterocyclic radical, these rings are further optional to be substituted with 1 to 3 following group that defines in the definition of these terms.

Term " alkoxyl group " is meant the Sauerstoffatom that is replaced by the alkyl of as defined in this Application alkyl or replacement.For example, term " alkoxyl group " comprises-O-C _1-6Alkyl.

Term " alkyl sulfenyl " is meant the sulphur atom that is replaced by the alkyl of as defined in this Application alkyl or replacement.For example, term " alkyl sulfenyl " comprises-S-C _1-6Alkyl etc.

Term " alkylamino " is meant the amino of the alkyl that is substituted with alkyl as defined above or replacement.For example, term " alkylamino " comprises-NR-C _1-12Alkyl (wherein R is preferably hydrogen but can comprises alkyl as defined above or the alkyl of replacement).

When subscript was used with alkoxyl group, alkyl sulfenyl or alkylamino, described subscript was meant the carbonatoms that described group can contain except that heteroatoms.Therefore, monovalence C for example _1-2Alkylamino comprises-CH ₂-N (CH ₃) ₂With-(CH ₂) ₂-NH ₂Low-grade alkyl amino comprises the alkylamino with 1 to 4 carbon atom.Term (C _1-4Alkyl) _0-2Amino comprises NH ₂,-NH (C _1-4Alkyl) and-N (C _1-4Alkyl) ₂" amino " that uses is meant NH separately ₂" amino of replacement " is meant the amino that replaces as described in the nitrogen-atoms in the above just inferior assorted alkyl chain, and comprises for example term alkylamino and acyl amino (NR _dC (O) R _e).When nothing further defined when pointing out amino to be mono-substituted, the residue valence link of nitrogen satisfied with hydrogen.For example, term " alkyl amino-carbonyl (halo) _0-1Aryl " group with following general formula described:

Alkoxyl group, alkyl sulfenyl or alkylamino can be monovalence or divalence." monovalence " is meant that the valency (promptly with another group bonded ability) of described group is 1, and " divalence " is meant that the valency of described group is 2.Therefore, for example the monovalence alkoxyl group comprises such as-O-C _1-12The group that alkyl is such, and the divalence alkoxyl group comprises such as-O-C _1-12Alkylidene group-such group.

It should be understood that those skilled in the art can select to obtain stable compound all groups (comprising for example alkoxyl group, alkyl sulfenyl and alkylamino).Therefore, for example in formula I compound, when G links to each other with the nitrogen-atoms (N*) of ring among the A and is selected from alkoxyl group or alkyl sulfenyl, described alkoxyl group and alkyl sulfenyl will have at least one and the carbon atom that encircles A (at the N* place) Direct Bonding, and described Sauerstoffatom or sulphur atom are at least one atoms away from described nitrogen-atoms.

Term " carbonyl " be meant divalence carbonyl-C (=O)-.When term " carbonyl " used with another group, such as in " heterocyclic radical carbonyl ", this combination had more clearly defined at least one substituting group that carbonyl contained that replaces.For example, " heterocyclic radical carbonyl " is meant carbonyl as defined above, and wherein at least one substituting group is heterocyclic radical (such as a morpholinyl).

Term " acyl group " is meant the carbonyl that links to each other with organic group, more specifically is group C (=O) R _eRadicals R _eThe alkyl of the defined alkyl of optional the application freely, thiazolinyl, alkynyl, alkylamino, replacement (i.e. the alkylidene group of Qu Daiing), the thiazolinyl that replaces, alkynyl, cycloalkyl, heterocyclic radical, aryl or the heteroaryl of replacement.Work as R _eDuring for aryl, heteroaryl, cycloalkyl or heterocyclic radical, these rings are further optional to be substituted with following one to three group that defines in the definition of these terms.

Term " alkoxy carbonyl " is meant the carboxyl that links to each other with organic group

(CO ₂R _e) and divalent group-CO of linking to each other with organic group in the formula I compound ₂-and-CO ₂R _e-, R wherein _eAs above define with regard to acyl group.The organic group that links to each other with carboxyl can be univalent (for example-CO ₂-alkyl or-OC (=O) alkyl) maybe can be divalence (for example-CO ₂-alkylidene group ,-OC (=O) alkylidene group etc.).Therefore, in formula I compound, when description G can be " alkoxy carbonyl ", it was intended to comprise that G is-CO ₂-and-CO ₂R _e-or-R _eCO ₂-selection, wherein be-CO at G ₂R _e-or-R _eCO ₂-situation under, radicals R _eTo be selected from divalent group, for example the alkynylene of the alkenylene of the alkylidene group of the alkylamino of alkylidene group, alkenylene, alkynylene, divalence, replacement, replacement or replacement.

Term " alkylsulfonyl " is meant (S (O) of sulfuryl group that links to each other with organic group in the formula I compound ₂-), more specifically be univalent perssad-S (O) ₂-R _eSimilarly, term " sulfinyl " is meant the group (S (O)-) that links to each other with organic group in the formula I compound, more specifically is univalent perssad-S (O)-R _eIn addition, alkylsulfonyl or sulfinyl can be divalence, R in this case _eBe the chemical combination key.Radicals R _eBe selected from as above with regard to acyl group and described those groups of alkoxy carbonyl, but get rid of R _eSituation for hydrogen.

Term " cycloalkyl " is meant saturated fully and the undersaturated hydrocarbon ring (so term " cycloalkyl " comprises the hydrocarbon ring that is also referred to as " cyclenes basic ring ") with the individual carbon atom of 3 to 9 (being preferably 3 to 7) of part.Term " cycloalkyl " comprise have zero, one, two or three substituent rings, described substituting group be selected from alkyl, thiazolinyl, the replacement of halogen, trifluoromethyl, trifluoromethoxy, alkyl, replacement thiazolinyl, alkynyl, nitro, cyano group, oxo (=O), OR _a, SR _a, (=S) ,-NR _aR _b,-N (alkyl) ₃ ⁺,-NR _aSO ₂,-NR _aSO ₂R _c,-SO ₂R _c,-SO ₂NR _aR _b,-SO ₂NR _aC (=O) R _b, SO ₃H ,-PO (OH) ₂,-C (=O) R _a,-CO ₂R _a,-C (=O) NR _aR _b,-C (=O) (C _1-4Alkylidene group) NR _aR _b,-C (=O) NR _a(SO ₂) R _b,-CO ₂(C _1-4Alkylidene group) NR _aR _b,-NR _aC (=O) R _b,-NR _aCO ₂R _b,-NR _a(C _1-4Alkylidene group) CO ₂R _b,=N-OH ,=N-O-alkyl, aryl, cycloalkyl, heterocyclic radical and/or heteroaryl, wherein R _a, R _bAnd R _cAs above the alkyl that just replaces defines, and further choosing wantonly is substituted also as described in the definition of top alkyl in replacement.Term " cycloalkyl " also comprises having with Cycloalkylfused second ring (for example comprising phenyl ring, heterocycle or hetero-aromatic ring) or have the ring of carbon-to-carbon bridge (described bridge has 3 to 4 carbon atoms).When cycloalkyl substituted has another ring (or having and second ring of its condensed), further optional 1 to 2 of being substituted with in the following group of described ring: (C _1-4) alkyl, (C _2-4) thiazolinyl, (C _2-4) alkynyl, halogen, hydroxyl, cyano group, nitro, CF ₃, O (C _1-4Alkyl), OCF ₃, C (=O) H, C (=O) (C _1-4Alkyl), CO ₂H, CO ₂(C _1-4Alkyl), NHCO ₂(C _1-4Alkyl) ,-S (C _1-4Alkyl) ,-NH ₂, NH (C _1-4Alkyl), N (C _1-4Alkyl) ₂, N (C _1-4Alkyl) ₃ ⁺, SO ₂(C _1-4Alkyl), C (=O) (C _1-4Alkylidene group) NH ₂, C (=O) (C _1-4Alkylidene group) NH (alkyl), C (=O) (C _1-4Alkylidene group) N (C _1-4Alkyl) ₂And/or the optional phenyl that is substituted with any aforementioned group.When valency allowed, if described another ring is cycloalkyl or heterocyclic radical, then it was also chosen wantonly and is substituted with=O (oxo).

Therefore, in formula I compound, term " cycloalkyl " comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, two ring octyl groups etc. and following ring system:

Deng, its any available atom place that can choose wantonly in described ring is substituted.

Preferred cycloalkyl comprise cyclopropyl, cyclopentyl, cyclohexyl and

Term " halo " or " halogen " are meant chlorine, bromine, fluorine and iodine.

Term " haloalkyl " expression has the alkyl of the replacement of one or more halogenic substituents.For example, " haloalkyl " comprises single methyl fluoride, difluoromethyl and trifluoromethyl.

Term " halogenated alkoxy " expression has the alkoxyl group of one or more halogenic substituents.For example, " halogenated alkoxy " comprises OCF ₃

Term " aryl " is meant phenyl, xenyl, fluorenyl, naphthalene-1-base and naphthalene-2-base.Term " aryl " comprise have zero, one, two or three substituent rings, described substituting group is selected from alkyl, thiazolinyl, the thiazolinyl of replacement, alkynyl, nitro, cyano group, the OR of halogen, trifluoromethyl, trifluoromethoxy, alkyl, replacement _a, SR _a, (=S), SO ₃H ,-NR _aR _b,-N (alkyl) ₃ ⁺,-NR _aSO ₂,-NR _aSO ₂R _c,-SO ₂R _c,-SO ₂NR _aR _b,-SO ₂NR _aC (=O) R _b, SO ₃H ,-PO (OH) ₂,-C (=O) R _a,-CO ₂R _a,-C (=O) NR _aR _b,-C (=O) (C _1-4Alkylidene group) NR _aR _b,-C (=O) NR _a(SO ₂) R _b,-CO ₂(C _1-4Alkylidene group) NR _aR _b,-NR _aC (=O) R _b,-NR _aCO ₂R _b,-NR _a(C _1-4Alkylidene group) CO ₂R _b, aryl, cycloalkyl, heterocyclic radical and/or heteroaryl, wherein R _a, R _bAnd R _cAs above the alkyl that just replaces defines, and also further optional as mentioned above being substituted.In addition, two substituting groups that link to each other with aryl (particularly phenyl) can combine to form another such as condensed ring or the such ring of volution, for example cyclopentyl or cyclohexyl or condensed heterocycle base or condensed heteroaryl.When aryl is substituted with another ring (or having and second ring of its condensed), further optional 1 to 2 of being substituted with in the following group of described ring: (C _1-4) alkyl, (C _2-4) thiazolinyl, (C _2-4) alkynyl, halogen, hydroxyl, cyano group, nitro, CF ₃, O (C _1-4Alkyl), OCF ₃, C (=O) H, C (=O) (C _1-4Alkyl), CO ₂H, CO ₂(C _1-4Alkyl), NHCO ₂(C _1-4Alkyl) ,-S (C _1-4Alkyl) ,-NH ₂, NH (C _1-4Alkyl), N (C _1-4Alkyl) ₂, N (C _1-4Alkyl) ₃ ⁺, SO ₂(C _1-4Alkyl), C (=O) (C _1-4Alkylidene group) NH ₂, C (=O) (C _1-4Alkylidene group) NH (alkyl), C (=O) (C _1-4Alkylidene group) N (C _1-4Alkyl) ₂And/or the optional phenyl that is substituted with any aforementioned group.When valency allowed, if described another ring is cycloalkyl or heterocyclic radical, then it was also chosen wantonly and is substituted with=O (oxo).

Therefore, the example of aryl comprises

(fluorenyl) etc., it can be chosen wantonly at any available carbon atom or any available nitrogen-atoms place and be substituted.Preferred aryl groups is the optional phenyl that replaces.

Term " Heterocyclylalkyl ", " heterocyclic radical " or " heterocycle " are used interchangeably and are meant and replace and 7 to 11 yuan of bicyclic groups of 3 to 7 yuan of monocyclic groups, replacement and unsubstituted non-aromatics of unsubstituted non-aromatics and 10 to 15 yuan of three cyclic groups of replacement and unsubstituted non-aromatics, wherein at least one ring has at least one heteroatoms (O, S or N), contains described heteroatomic ring and preferably has 1,2 or 3 heteroatoms that is selected from O, S and N.The containing heteroatomic each ring and can contain 1 or 2 Sauerstoffatom or sulphur atom and/or 1 to 4 nitrogen-atoms of heterocyclic radical, condition is that the heteroatoms sum in each ring is no more than 4, and another condition is that described ring contains at least one carbon atom.Nitrogen-atoms and sulphur atom can be chosen wantonly oxidized and nitrogen-atoms can be chosen wantonly by quaternized.The condensed ring of formation bicyclic groups and three cyclic groups can only contain carbon atom and can be saturated, fractional saturation or undersaturated.Heterocyclic radical can be connected at any available nitrogen-atoms or any available carbon atom place.Heterocyclic ring can contain zero, one, two or three substituting groups, described substituting group be selected from alkyl, thiazolinyl, the replacement of halogen, trifluoromethyl, trifluoromethoxy, alkyl, replacement thiazolinyl, alkynyl, nitro, cyano group, oxo (=O), OR _a, SR _a, (=S) ,-NR _aR _b,-N (alkyl) ₃ ⁺,-NR _aSO ₂,-NR _aSO ₂R _c,-SO ₂R _c,-SO ₂NR _aR _b,-SO ₂NR _aC (=O) R _b, SO ₃H ,-PO (OH) ₂,-C (=O) R _a,-CO ₂R _a,-C (=O) NR _aR _b,-C (=O) (C _1-4Alkylidene group) NR _aR _b,-C (=O) NR _a(SO ₂) R _b,-CO ₂(C _1-4Alkylidene group) NR _aR _b,-NR _aC (=O) R _b,-NR _aCO ₂R _b,-NR _a(C _1-4Alkylidene group) CO ₂R _b,=N-OH ,=N-O-alkyl, aryl, cycloalkyl, heterocyclic radical and/or heteroaryl, wherein R _a, R _bAnd R _cAs above the alkyl that just replaces defines, and also further optional as mentioned above being substituted.When heterocyclic radical is substituted with another ring, further optional 1 to 2 of being substituted with in the following group of described ring: (C _1-4) alkyl, (C _2-4) thiazolinyl, (C _2-4) alkynyl, halogen, hydroxyl, cyano group, nitro, CF ₃, O (C _1-4Alkyl), OCF ₃, C (=O) H, C (=O) (C _1-4Alkyl), CO ₂H, CO ₂(C _1-4Alkyl), NHCO ₂(C _1-4Alkyl) ,-S (C _1-4Alkyl) ,-NH ₂, NH (C _1-4Alkyl), N (C _1-4Alkyl) ₂, N (C _1-4Alkyl) ₃ ⁺, SO ₂(C _1-4Alkyl), C (=O) (C _1-4Alkylidene group) NH ₂, C (=O) (C _1-4Alkylidene group) NH (alkyl), C (=O) (C _1-4Alkylidene group) N (C _1-4Alkyl) ₂And/or the optional phenyl that is substituted with any aforementioned group.When valency allowed, if described another ring is cycloalkyl or heterocyclic radical, then it was also chosen wantonly and is substituted with=O (oxo).

Monocyclic groups comprise azetidinyl, pyrrolidyl, oxetanyl, imidazolinyl, Oxazolidinyl, different

Azoles quinoline base, thiazolidyl, isothiazole alkyl, tetrahydrofuran base, piperidyl, piperazinyl, 2-oxo piperazinyl, 2-oxo-piperidine base, 2-oxo-pyrrolidine base, 2-oxo azepine

Base, azepine

Base, 4-piperidone base, THP trtrahydropyranyl, morpholinyl, parathiazan base, S-oxo parathiazan base (thiamorpholinyl sulfoxide), S, S-dioxo parathiazan base (thiamorpholinyl sulfone), 1,3-dioxolane base and tetrahydrochysene-1,1-dioxo thienyl etc.Exemplary bicyclic heterocycles base comprises quinuclidinyl.

Heterocyclic radical in the formula I compound comprises

It can be chosen wantonly and be substituted.

Term " heteroaryl " is meant and replaces and 9 or 10 yuan of bicyclic groups of 5 or 6 yuan of monocyclic groups, replacement and unsubstituted aromatics of unsubstituted aromatics and 11 to 14 yuan of three cyclic groups of replacement and unsubstituted aromatics, it has at least one heteroatoms (O, S or N) at least one ring, contain described heteroatomic ring and preferably have 1,2 or 3 heteroatoms that is selected from O, S and N.The containing heteroatomic each ring and can contain 1 or 2 Sauerstoffatom or sulphur atom and/or 1 to 4 nitrogen-atoms of heteroaryl, condition is that the heteroatoms sum in each ring is no more than 4, and each ring has at least one carbon atom.The condensed ring of formation bicyclic groups and three cyclic groups can only contain carbon atom and can be saturated, fractional saturation or undersaturated.Nitrogen-atoms and sulphur atom can be chosen wantonly oxidized and nitrogen-atoms can be chosen wantonly by quaternized.Bicyclic heteroaryl or tricyclic heteroaryl must comprise the ring of at least one Wholly aromatic, but other one or more condensed ring can be aromatics or non-aromatics.Heteroaryl can be connected in any available nitrogen-atoms or any available carbon atom place in any ring.The heteroaryl ring system can contain zero, one, two or three substituting groups, and described substituting group is selected from alkyl, thiazolinyl, the thiazolinyl of replacement, alkynyl, nitro, cyano group, the OR of halogen, trifluoromethyl, trifluoromethoxy, alkyl, replacement _a, SR _a, (=S) ,-NR _aR _b,-N (alkyl) ₃ ⁺,-NR _aSO ₂,-NR _aSO ₂R _c,-SO ₂R _c,-SO ₂NR _aR _b,-SO ₂NR _aC (=O) R _b, SO ₃H ,-PO (OH) ₂,-C (=O) R _a,-CO ₂R _a,-C (=O) NR _aR _b,-C (=O) (C _1-4Alkylidene group) NR _aR _b,-C (=O) NR _a(SO ₂) R _b,-CO ₂(C _1-4Alkylidene group) NR _aR _b,-NR _aC (=O) R _b,-NR _aCO ₂R _b,-NR _a(C _1-4Alkylidene group) CO ₂R _b, aryl, cycloalkyl, heterocyclic radical and/or heteroaryl, wherein R _a, R _bAnd R _cAs above the alkyl that just replaces defines, and also further optional as mentioned above being substituted.When heteroaryl is substituted with another ring, further optional 1 to 2 of being substituted with in the following group of described ring: (C _1-4) alkyl, (C _2-4) thiazolinyl, (C _2-4) alkynyl, halogen, hydroxyl, cyano group, nitro, CF ₃, O (C _1-4Alkyl), OCF ₃, C (=O) H, C (=O) (C _1-4Alkyl), CO ₂H, CO ₂(C _1-4Alkyl), NHCO ₂(C _1-4Alkyl) ,-S (C _1-4Alkyl) ,-NH ₂, NH (C _1-4Alkyl), N (C _1-4Alkyl) ₂, N (C _1-4Alkyl) ₃ ⁺, SO ₂(C _1-4Alkyl), C (=O) (C _1-4Alkylidene group) NH ₂, C (=O) (C _1-4Alkylidene group) NH (alkyl), C (=O) (C _1-4Alkylidene group) N (C _1-4Alkyl) ₂And/or the optional phenyl that is substituted with any aforementioned group.When valency allowed, if described another ring is cycloalkyl or heterocyclic radical, then it was also chosen wantonly and is substituted with=O (oxo).

Bicyclic heteroaryl comprise pyrryl, pyrazolyl, pyrazolinyl, imidazolyl,

Azoles base, different

Azoles base, thiazolyl, thiadiazolyl group, isothiazolyl, furyl, thienyl,

Di azoly, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, triazinyl etc.

Bicyclic heteroaryl comprises indyl, benzothiazolyl, benzodioxole base, benzo Azoles base, benzothienyl, quinolyl, tetrahydro isoquinolyl, isoquinolyl, benzimidazolyl-, benzopyranyl, indolizine base, benzofuryl, chromone base, tonka bean camphor base, benzopyranyl, cinnolines base, quinoxalinyl, indazolyl, pyrrolopyridinyl, furo pyridyl, dihydro-iso indolyl, tetrahydric quinoline group etc.

Exemplary tricyclic heteroaryl comprises carbazyl, benzindole base, phenanthroline base, acridyl, phenanthridinyl, xanthenyl etc.

In formula I compound, preferred heteroaryl comprises

Deng, it can be chosen wantonly at any available carbon atom or any available nitrogen-atoms place and be substituted.Aromatic ring also can be represented by the complete circle in the ring.

Except as otherwise noted, when the aryl (for example phenyl) of mentioning clearly name, cycloalkyl (for example cyclohexyl), heterocyclic radical (for example pyrrolidyl, piperidyl and morpholinyl) or heteroaryl (for example tetrazyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl and furyl), unless expressly stated otherwise,, described mentioning is intended to comprise to have the individual substituent ring of 0 to 3 (being preferably 0-2), and described substituting group is selected from top with regard to described those substituting groups of aryl, cycloalkyl, heterocyclic radical and/or heteroaryl according to circumstances.

Term " heteroatoms " should comprise oxygen, sulphur and nitrogen.

Saturated or undersaturated two rings of the saturated or undersaturated monocycle of term " carbocyclic ring " expression, wherein all atoms in all rings are carbon.Therefore, described term comprises cycloalkyl ring and aryl rings.Carbocyclic ring can be substituted, and wherein substituting group is selected from top with regard to cycloalkyl and described those substituting groups of aryl.

When the application used term " unsaturated " to come trimming loop or group, described ring or group can be unsaturated fully or part is undersaturated.

" choose wantonly and replace " when coming trimming loop or group when the application uses term, described ring or group can be replacements or unsubstituted.

In entire description, those skilled in the art can select group and substituting group thereof to obtain stable part and compound and to can be used as the compound of pharmaceutically acceptable compound and/or can be used for preparing the midbody compound of pharmaceutically acceptable compound.

Formula I compound can form salt, and it also within the scope of the present invention.Except as otherwise noted, it should be understood that mentioned The compounds of this invention comprises its salt.Term " salt " the expression acid salt and/or the base addition salt of mineral acid and/or organic acid and mineral alkali and/or organic bases formation.In addition, for example when formula I compound not only contained basic moiety (such as amine or pyridine ring or imidazole ring) but also contains acidic moiety (such as carboxylic acid), term " salt " can comprise zwitter-ion (inner salt).Pharmacologically acceptable salt (be nontoxic and physiology on acceptable salt) is preferred, and such as acceptable metal-salt and amine salt, wherein positively charged ion does not significantly encourage the toxicity or the biological activity of described salt.Yet for example with regard to regard to spendable isolated or purified step in the preparation process, other salt can be useful, so they also within the scope of the present invention.The salt of formula I compound for example can followingly form: make the acid of formula I compound and a certain amount of (such as monovalent) or alkali in the sedimentary therein medium of medium such as salt or react in aqueous medium, then carry out freeze-drying.

Exemplary acid salt comprises acetate (such as those salt that form with acetate or three halogenated acetic acids (for example trifluoroacetic acid)), adipic acid salt, alginate, ascorbate salt, aspartate, benzoate, benzene sulfonate, hydrosulfate, borate, butyrates, citrate, camphorate, camsilate, cyclopentane propionate, digluconate, dodecyl sulfate, esilate, fumarate, gluceptate, glycerophosphate, Hemisulphate, enanthate, hexanoate, hydrochloride (forming) with hydrochloric acid, hydrobromate (forming) with hydrogen bromide, hydriodate, the 2-isethionate, lactic acid salt, maleate (forming) with toxilic acid, mesylate (forming) with methylsulfonic acid, naphthalene-2-sulfonic acid salt, nicotinate, nitrate, oxalate, pectate, persulphate, 3-phenylpropionic acid salt, phosphoric acid salt, picrate, pivalate, propionic salt, salicylate, succinate, vitriol (such as those salt that form with sulfuric acid), sulfonate (those sulfonate of mentioning such as the application), tartrate, thiocyanate-, tosylate (such as tosilate), undecane hydrochlorate etc.

Exemplary base addition salt comprises ammonium salt; An alkali metal salt is such as sodium salt, lithium salts and sylvite; Alkaline earth salt is such as calcium salt and magnesium salts; Barium salt, zinc salt and aluminium salt; Salt with organic bases (for example organic amine) formation, described organic bases is such as trialkylamine (such as triethylamine), PROCAINE HCL, PHARMA GRADE, dibenzyl amine, N-benzyl-β-styroyl amine, 1-ephenamine, N, N '-dibenzyl-ethylenediamin, dehydroabietylamine, N-ethylpiperidine, benzyl amine, dicyclohexylamine or similar pharmaceutically acceptable amine; With the salt that forms with amino acid (such as arginine, Methionin etc.).The alkalescence nitrogen-containing group can be quaternized with following reagent: such as elementary alkyl halide (methyl chloride for example, ethyl chloride, propyl chloride, Butyryl Chloride, monobromomethane, monobromoethane, propyl bromide, butyl bromide, methyl-iodide, iodoethane, propyl iodide and butyl iodide), sulfuric acid dialkyl (methyl-sulfate for example, ethyl sulfate, dibutyl sulfate and sulfuric acid diamyl ester), long-chain halogenide (decyl chloride for example, lauryl chloride, myristyl chlorine, stearyl chloride, decyl bromide, lauryl bromide, the myristyl bromine, the stearyl bromine, iododecane, lauryl iodine, myristyl iodine and stearyl iodine), aralkyl halide (for example bromotoluene and phenethyl bromide) etc.Preferred salt comprises mono-hydrochloric salts, hydrosulfate, mesylate, phosphoric acid salt or nitrate.

The prodrug of The compounds of this invention and solvate (for example hydrate) are also within the scope of the present invention.The compound that term " prodrug " expression is such, described compound experiences chemical conversion to obtain formula I compound and/or its salt and/or solvate by metabolic process or chemical process after being administered to the experimenter.Can transform with any compound that produces biologically active agent (being formula I compound) in vivo is prodrug in the scope of the invention and purport.For example, the compound that contains carboxyl can form hydrolyzable ester on the physiology, described ester by hydrolysis in vivo with production I compound itself as prodrug.Such prodrug preferred oral administration, this is because hydrolysis mainly takes place under the influence of digestive ferment as a rule.Administered parenterally can have under the situation that activity or hydrolysis take place in blood at ester itself and uses.The example of hydrolyzable ester comprises C on the physiology of formula I compound _1-6Alkyl benzyl ester, 4-methoxy-benzyl ester, indanyl ester, phthaloyl ester, methoxymethyl ester, C _1-6Alkyloyl oxygen base-C _1-6Alkyl ester (for example acetoxy-methyl ester, valeryl oxygen ylmethyl ester or propionyl oxygen ylmethyl ester), C _1-6Alkoxy-carbonyl oxy-C _1-6Hydrolyzable ester on alkyl ester (for example methoxycarbonyl-oxygen ylmethyl ester or ethoxy carbonyl oxygen ylmethyl ester), glycyl oxygen ylmethyl ester, phenyl glycyl oxygen ylmethyl ester, (5-methyl-2-oxo-1,3-Dioxol-4-yl)-methyl ester and other known physiology of for example in penicillin and cynnematin field, using.Such ester can prepare by routine techniques known in the art.

Various forms of prodrugs are known in the art.The example of aforementioned prodrugs derivative referring to:

A) Design of Prodrugs, edited by H.Bundgaard, (Elsevier, 1985) and Methodsin Enzymology, Vol.112, pp.309-396, edited by K.Widder, et al. (AcamedicPress, 1985);

B) A Textbook of Drug Design and Development, edited byKrosgaard-Larsen and H.Bundgaard, Chapter 5, " Design and Application ofProdrugs; " by H.Bundgaard, pp.113-191 (1991); With

c)H.Bundgaard，Advanced?Drug?Delivery?Reviews，Vol.8，pp.1-38(1992)，each?of?which?is?incorporated?herein?by?reference；

Incorporate above-mentioned every piece of document into this paper as a reference

Formula I compound and salt thereof can exist by their tautomeric form, wherein hydrogen atom be transferred in the molecule other parts and therefore in the molecule chemical bond between the atom reset.It should be understood that all tautomeric forms,, just comprise in the present invention as long as they can exist.In addition, The compounds of this invention can have trans-isomer(ide) and cis-isomeride and can contain one or more chiral centres, therefore exists with enantiomerism form and diastereo-isomerism form.The present invention includes the mixture of all such isomer and cis-isomeride and trans-isomer(ide), the mixture of diastereomer and the racemic mixture of enantiomer (optically active isomer).When the configuration that does not spell out compound (or asymmetric carbon) (cis or trans or R or S), be intended to represent any isomer or more than a kind of mixture of isomers.The preparation method can use racemic modification, enantiomer or diastereomer as raw material.When preparation enantiomerism product or diastereo-isomerism product, they can separate by ordinary method (for example chromatogram or fractional crystallization).

Combination

When needs, formula I compound can with therapeutical agent (for example immunosuppressor, carcinostatic agent, antiviral agent, anti-inflammatory agent, anti-mycotic agent, microbiotic, anti-angiogenic hyper-proliferative agent, antidepressive, lipid-lowering agent or lipid depressant or lipid regulating agent, antidiabetic, antiobesity agent, hypotensive agent, anticoagulant and/or the osteoporosis agent) coupling of one or more other types, they can be in same formulation or in the oral dosage form that is separating oral administration or drug administration by injection.

The immunosuppressor that can choose wantonly with formula I compound of the present invention coupling comprises ciclosporin (for example ciclosporin A), mycophenolate, interferon beta, deoxyspergolin, FK-506 or Ant.-IL-2.

The carcinostatic agent that can choose wantonly with formula I compound of the present invention coupling comprises that azathiprine, 5 FU 5 fluorouracil, endoxan, cis-platinum, methotrexate, thiophene are for group, carboplatin etc.

The antiviral agent that can choose wantonly with formula I compound of the present invention coupling comprises Abacavir, acyclovir, ganciclovir, zidanocin, vidarabine etc.

The anti-inflammatory agent that can choose wantonly with formula I compound of the present invention coupling comprises that nonsteroidal anti-inflammatory agent (NSAID) is such as Ibuprofen BP/EP, cox-2 inhibitor such as celecoxib, rofecoxib, acetylsalicylic acid, Naproxen Base, Ketoprofen, diclofenac sodium, indomethacin, piroxicam, steroid class such as prednisone, dexamethasone, hydrocortisone, Ledercort A, gold compound is such as disodium aurothiomalate, TNF-alpha inhibitor such as tenidap, anti-TNF antibodies or soluble TNF acceptor and rapamycin (sirolimus or Lei Paming) or derivatives thereof, Ying Fuli Xidan anti-(

Centocor, Inc), CTLA-4Ig, LEA29Y, antibody is such as anti-ICAM-3, anti-IL-2 acceptor (Anti-Tac), anti-CD45RB, anti-CD2, anti-CD3 (OKT-3), anti-CD4, anti-CD80, anti-CD86, monoclonal antibody OKT3, interactional medicine is such as the specific antibody at CD40 and/or CD154 between blocking-up CD40 and the CD154 (being also referred to as " gp39 "), fusion rotein is such as etanercept, by the fusion rotein (for example CD40Ig and CD8gp39) that CD40 and/or CD154gp39 make up, NF-κ B depressant of functions is such as nuclear translocation inhibitor such as Gusperimus (DSG).

The anti-mycotic agent that can choose wantonly with formula I compound of the present invention coupling comprises fluconazole, miconazole, amphotericin B etc.

The microbiotic that can choose wantonly with formula I compound of the present invention coupling comprises penicillin, tsiklomitsin, amoxycilline Trihydrate bp, Ampicillin Trihydrate, erythromycin, Vibravenos, vancomycin, Minocycline HCl, clindamycin or Cephalexin Monohydrate Micro/Compacted.

The anti-angiogenic hyper-proliferative agent that can choose wantonly with formula I compound of the present invention coupling comprises methotrexate, leflunomide, FK506 (Ta Luolimu, Prograf).

Can choose wantonly with the lipid-lowering agent of formula I compound of the present invention coupling or lipid depressant or lipid regulating agent and can comprise in the following medicine a kind, 2 kinds, 3 kinds or more kinds of: MTP inhibitor, HMG CoA reductase inhibitor, inhibitor for squalene synthetic enzyme, fiber acid derivative, ACAT inhibitor, lipoxidase inhibitor, cholesterol absorption inhibitor, ileum Na ⁺Adjustment on/bile acide cotransporter inhibitor, the ldl receptor activity, bile acid chelating agent and/or nicotinic acid and derivative thereof.

MTP inhibitor used in this application comprises the MTP inhibitor that discloses in following document: United States Patent (USP) 5,595,872, United States Patent (USP) 5,739,135, United States Patent (USP) 5,712,279, United States Patent (USP) 5,760, and 246, United States Patent (USP) 5,827,875, United States Patent (USP) 5,885, the U. S. application 09/175 that on October 20th, 983 and 1998 submitted to, 180 (now being United States Patent (USP) 5,962,440).The every kind of preferred L TP inhibitor that in above-mentioned every piece of patent and application, discloses preferably.

Incorporate above-mentioned all United States Patent (USP)s and application into this paper as a reference.

The most preferred MTP inhibitor that the present invention uses comprises United States Patent (USP) 5,739, the preferred L TP inhibitor of describing in 135,5,712,279 and 5,760,246.

Most preferred MTP inhibitor is 9-[4-[4-[[2-(2,2, a 2-trifluoro ethoxy) benzoyl] amino]-piperidino] butyl]-N-(2,2, the 2-trifluoroethyl)-9H-fluorenes-9-formyl ammonia:

Described lipid-lowering agent can be a HMG CoA reductase inhibitor, it includes but not limited to United States Patent (USP) 3,983, mevastatin that discloses in 140 and related compound, United States Patent (USP) 4,231, general Liprevil that discloses in lovastatin (Mevacor) that discloses in 938 and related compound, the United States Patent (USP) 4,346,227 and related compound, United States Patent (USP) 4,448, the Simvastatin and the related compound that disclose in 784 and 4,450,171.Spendable other HMG CoA reductase inhibitor of the application includes but not limited to United States Patent (USP) 5,354, the fluvastatin that discloses in 772, United States Patent (USP) 5,006,530 and 5,177, the Cerivastatin that discloses in 080, United States Patent (USP) 4,681,893,5,273,995,5,385,929 and 5,686, the atorvastatin that discloses in 104, United States Patent (USP) 5,011, the itavastatin that discloses in 930 (Buddhist nun of Nissan/Sankyo cut down him spit of fland (NK-104)), United States Patent (USP) 5,260, the Wei Shatating (ZD-4522) of the Shionogi-Astra/Zeneca that discloses in 440, United States Patent (USP) 5,753, the relevant statin compound that discloses in 675, United States Patent (USP) 4,613, the pyrazole analogs of the mevalonolactone derivative that discloses in 610, the indenes analogue of the mevalonolactone derivative that discloses among the PCT application WO 86/03488, United States Patent (USP) 4,647,6-[2-(pyrroles of replacement-1-the yl)-alkyl that discloses in 576) pyran-2-one and derivative thereof, the SC-45355 of Searle (glutaric acid derivatives that 3-replaces) dichloroacetate, the imidazoles analogue of the mevalonolactone that discloses among the PCT application WO 86/07054, French Patent 2,596,3-carboxyl-2-hydroxyl-propane-the phosphonate derivative that discloses in 393, disclose in the european patent application 0221025 2, the 3-disubstituted pyrroles, furans and thiophene derivant, United States Patent (USP) 4,686, the naphthyl analogue of the mevalonolactone that discloses in 237, United States Patent (USP) 4,499, the octahydro naphthalene compounds that discloses in 289, the keto analog and the United States Patent (USP) 5 of the Mevacor (lovastatin) that discloses among european patent application 0142146 A2,506,219 and 5, the quinoline and the pyridine derivate that disclose in 691,322.

In addition, in GB 2205837, disclosed the phosphinic compounds that can be used for suppressing HMG CoA reductase enzyme that is applicable to the application.

The inhibitor for squalene synthetic enzyme that is applicable to the application includes but not limited to United States Patent (USP) 5; 712; α-phosphono-the sulphonate that discloses in 396, Biller et al., J.Med.Chem.; Vol.31; those materials (comprising isoprenoid (phosphinyl-methyl) phosphonic acid ester) that disclose among the No.10, pp.1869-1871 (1988) and other known inhibitor for squalene synthetic enzyme are [as United States Patent (USP) 4; 871; 721 and 4,924,024 and Biller; S.A.; Neuenschwander, K., Ponpipom; M.M.; and Poulter, C.D., CurrentPharmaceutical Design; the inhibitor for squalene synthetic enzyme that discloses among the Vol.2, pp.1-40 (1996)].

In addition, other inhibitor for squalene synthetic enzyme that is applicable to the application comprises P.Ortiz deMontellano et al., J.Med.Chem., 1977,20, the terpenoid pyrophosphate that discloses among the 243-249, Corey and Volante, J.Am.Chem.Soc., 98, the farnesyl bisphosphate analogue A and preceding squalene pyrophosphate (PSQ-PP) analogue that disclose among the 1291-1293 (1976), McClard, R.W.et al., J.Am.Chem.Soc., the phosphinyl phosphonic acid ester that discloses in 1987,109,5544 (1987), and Capson, T.L., PhD dissertation, Dept.Med.Chem.U.of Utah, Abstract, Table of Contents, pp.16,17,40-43, the cyclopropanes compound that discloses among the 48-51, Summary (June, 1987).

Other lipid-lowering agent that is applicable to the application includes but not limited to fiber acid derivative such as fenofibrate, gemfibrozil, clofibrate, bezafibrate, Win-35833, S-8527 etc., United States Patent (USP) 3, the probucol that discloses in 674,836 and related compound (probucol and gemfibrozil are preferred), bile acid chelating agent such as Colestyramine, colestipol and DEAE-Sephadex (

Or

) and Cholestagel (Sankyo/Geltex) and guarantor's fat appropriate (Rhone-Poulenc), EisaiE-5050 (ethanolamine derivant that N is substituted), imanixil (HOE-402), tetrahydrochysene presses down fat element (THL), istigmastanylphos-phorylcholine (SPC, Roche), amino cyclodextrin (Tanabe Seiyoku), Ajinomoto AJ-814 (azulene derivatives), AC-233 (Sumitomo), Sandoz 58-035, American Cyanamid CL-277,082 and CL-283,546 (dibasic urea derivativess), nicotinic acid, acipimox, Acifran, Xin Meisu, para-aminosalicylic acid, acetylsalicylic acid, United States Patent (USP) 4,759, poly-(diallyl methylamine) derivative that discloses in 923, quaternary amine gathers (diallyldimethylammonium chloride) and United States Patent (USP) 4, the ionene and other the known serum cholesterol lowering agent that disclose in 027,009.

Described lipid-lowering agent can be ACAT inhibitor or the TS-962 (N-[2 that discloses in the following document, 6-two (1-methylethyl) phenyl]-2-(tetradecyl sulfenyl)-ethanamide) (Taisho Pharmaceutical Co.Ltd): Drugs of the Future, 24,9-15 (1999), (avasimibe); " The ACAT inhibitor; Cl-1011 is effective in the prevention and regression of aortic fatty streak area inhamsters ", Nicolosi et al., Atherosclerosis (Shannon, Irel) .137 (1), 77-85 (1998); " The pharmacological profile of FCE 27677:a novel ACAT inhibitor with potenthypolipidemic activity mediated by selective suppression of the hepatic secretionof ApoB 100-containing lipoprotein ", Ghiselli, Giancarlo, Cardiovasc.DrugRev. (1998), 16 (1), 16-30; " RP 73163:a bioavailablealkylsulfinyl-diphenylimidazole ACAT inhibitor ", Smith, C., et al, Bioorg.Med.Chem.Lett.6 (1), 47-50 (1996); " ACAT inhibitors:physiologic mechanisms forhypolipidemic and anti-atherosclerotic activities in experimental animals ", Krause et al, Editor (s): Ruffolo, Robert R., Jr.; Hollinger, Mannfred A., Inflammation:Mediators Pathways 173-98 (1995), Publisher:CRC, Boca Raton, Fla.; " ACAT inhibitors:potential anti-atherosclerotic agents ", Sliskovic et al, Curr.Med.Chem.1 (3), 204-251994); " Inhibitors of acyl-CoA:cholesterolO-acyl transferase (ACAT) as hypocholesterolemic agents.6.The firstwater-soluble ACAT inhibitor with lipid-regulating activity.Inhibitors ofacyl-CoA:cholesterol acyltransferase (ACAT) .7.Development of a series ofsubstituted N-phenyl-N '-[(1-phenylcyclopentyl) methyl] ureas with enhancedhypocholesterolemic activity ", Stout et al, Chemtracts:Org.Chem.8 (6), 359-62 (1995).

Described lipid-lowering agent can be to adjust on the LD2 receptor active, such as MD-700 (3-(13-hydroxyl-10-oxo tetradecyl)-5,7-dimethoxy isobenzofuran-1 (3H)-ketone) (TaishoPharmaceutical Co.Ltd) and LY295427 (4-(2-propenyl)-(3a, 4a, 5a)-cholestane-3-alcohol) (EliLilly).

Described lipid-lowering agent can be a cholesterol absorption inhibitor, be preferably ezetimibe (SCH58235) and SCH48461 and the Atherosclerosis 115 of Schering-Plough, 45-63 (1995) and J.Med.Chem.41,973 (1998) middle those materials that disclose.

Described lipid-lowering agent can be ileum Na ⁺/ bile acide cotransporter inhibitor, as Drugs ofthe Future, 24, those materials that disclose among the 425-430 (1999).

Described lipid regulating agent can be cetp (CETP) inhibitor, such as the CP 529,414 (torcetrapib) (WO/0038722 and EP 818448) of Pfizer and SC-744 and the SC-795 of Pharmacia.

The ATP Citric Acid lyase inhibitors that can be used for the present invention combination can comprise those materials that disclose in the United States Patent (USP) 5,447,954 for example.

Preferred lipid-lowering agent is general Liprevil, lovastatin, Simvastatin, atorvastatin, fluvastatin, Cerivastatin, itavastatin and visastatin and ZD-4522.

Incorporate above-mentioned United States Patent (USP) into this paper as a reference.Employed amount and dosage are as pointed in Physician ' sDesk Reference and/or above-mentioned patent.

The weight ratio of formula I compound of the present invention and lipid-lowering agent (if existence) can be about 500: 1 to about 1: 500, is preferably about 100: 1 to about 1: 100.

Dosage must carefully be adjusted according to patient's age, body weight and state and route of administration, formulation and dosage regimen and desired result.

Disclosed in the dosage of lipid-lowering agent and preparation such as above-mentioned each piece patent and the application.

Dosage of used other lipid-lowering agent (if use) and preparation are pointed in can Physician ' the sDesk Reference as latest edition.

For oral administration, satisfied result can use the MTP inhibitor of following amount to obtain: about 0.01mg is to about 500mg, and is preferably extremely about 100mg of about 0.1mg, wherein every day 1 to 4 time.

The amount of the MTP inhibitor that preferred oral dosage form (for example tablet or capsule) is contained can be about 1 to about 500mg, is preferably about 2 to about 400mg, and more preferably about 5 to about 250mg, wherein every day 1 to 4 time.

For oral administration, satisfied result can use HMG CoA reductase inhibitor (for example general Liprevil, lovastatin, Simvastatin, atorvastatin, fluvastatin or Cerivastatin) to obtain, and described HMG CoA reductase inhibitor uses with the dosage pointed out among Physician ' the s Desk Reference (all according to appointment 1 to 2000mg and be preferably about 4 to about 200mg).

The using dosage of described inhibitor for squalene synthetic enzyme can be 10mg to about 2000mg, and is preferably about 25mg to about 200mg.

The amount of the HMG CoA reductase inhibitor that preferred oral dosage form (such as tablet or capsule) is contained can be about 0.1 to about 100mg, is preferably about 0.5 to about 80mg, and more preferably about 1 to about 40mg.

The amount of the inhibitor for squalene synthetic enzyme that preferred oral dosage form (such as tablet or capsule) is contained can be about 10 to about 500mg, is preferably about 25 to about 200mg.

Described lipid-lowering agent also can be the lipoxidase inhibitor that comprises 15-lipoxygenase (15-LO) inhibitor, as the benzimidizole derivatives that discloses among the WO 97/12615, the 15-LO inhibitor that discloses among the WO 97/12613, the isothiazolones and the Sendobry etal " Attenuation of diet-induced atherosclerosis in rabbits with a highly selective15-lipoxygenase inhibitor lacking significant antioxidant properties " that disclose among the WO 96/38144, Brit.J.Pharmacology 120,1199-1206 (1997) and Cornicelli et al, " 15-Lipoxygenase andits Inhibition:A Novel Therapeutic Target for Vascular Disease ", CurrentPharmaceutical Design, 5, the 15-LO inhibitor that discloses among the 11-20 (1999).

Formula I compound and lipid-lowering agent can use in same oral dosage form or use by taking together simultaneously with the oral dosage form that separates together.

Above-mentioned composition can come administration with single dose or broken dose (every day 1 to 4 time) by above-mentioned formulation.Make the patient start from the low dose group merging and increase to the high dosage combination gradually, this may be desirable.

Preferred lipid-lowering agent is general Liprevil, Simvastatin, lovastatin, atorvastatin, fluvastatin or Cerivastatin and nicotinic acid and/or Cholestagel.

Can choose other antidiabetic with the coupling of formula I compound wantonly and can be a kind in following antidiabetic or the antihyperglycemic agents, 2 kinds, 3 kinds or more kinds of: Regular Insulin succagoga or euglycemic agent or the mechanism of action are preferably other antidiabetic different with formula I compound of the present invention, and described other antidiabetic can comprise biguanide compound, sulfonyl urea compound, glucosidase inhibitor, the PPAR gamma agonist is such as thiazolidine dione compounds, the aP2 inhibitor, DPP IV (DP4) inhibitor, SGLT2 inhibitor and/or meglitinide compounds and Regular Insulin and/or glucagon-like peptide-1 (GLP-1).

Other antidiabetic can be oral antihyperglycemic agents, is preferably biguanide compound such as N1,N1-Dimethylbiguanide or phenformin or its salt, is preferably Walaphage.

At described antidiabetic is under the situation of biguanide compound, and the weight ratio of formula I compound and biguanide compound can be about 0.001: 1 to about 10: 1, is preferably about 0.01: 1 to about 5: 1.

Other antidiabetic also can be preferably sulfonyl urea compound such as Glyburide (being also referred to as glyburide), glimepiride (at United States Patent (USP) 4,379, disclose in 785), Glipizide, gliclazide or P-607, other known sulfonyl urea compound or act on other antihyperglycemic agents of beta cell ATP dependency passage, wherein Glyburide and Glipizide are preferred, and it can come administration by same oral dosage form or the oral dosage form that separates.

The weight ratio of formula I compound and sulfonyl urea compound can be about 0.01: 1 to about 100: 1, is preferably about 0.02: 1 to about 5: 1.

Oral antidiabetic also can be glucosidase inhibitor such as acarbose (at United States Patent (USP) 4,904,769 in disclose) or miglitol (at United States Patent (USP) 4,639,436 in disclose), and it can come administration by same oral dosage form or the oral dosage form that separates.

The weight ratio of formula I compound and glucosidase inhibitor can be about 0.01: 1 to about 100: 1, is preferably about 0.05: 1 to about 10: 1.

Formula I compound can with following drug combination: PPAR gamma agonist such as thiazolidinedione oral antidiabetic or other euglycemic agent (it has insulin-sensitizing effect in NIDDM patient) such as troglitazone be (Warner-Lambert's

[at United States Patent (USP) 4,572, disclose in 912]), the MCC-555 of rosiglitazone (SKB), pioglitazone (Takeda), Mitsubishi is (at United States Patent (USP) 5,594, disclosure in 016), GL-262570 (farglitazar), the englitazone (CP-68722 of Glaxo-Wellcome, Pfizer), darglitazone (CP-86325, Pfizer), isaglitazone (MIT/J ﹠amp; J), JTT-501 (Rui Geliezha) (JPNT/P; U), L-895645 (Merck), R-119702 (Li Gelie ketone) (Sankyo/WL), NN-2344 (Ba Gelie ketone) (Dr.Reddy/NN) or YM-440 ((Z)-1,4-two-4-[(3,5-dioxo-1,2,4-

Azoles alkane-2-base-methyl)]-and the phenoxy group but-2-ene) (Yamanouchi), be preferably rosiglitazone and pioglitazone.

The weight ratio of formula I compound and thiazolidine dione compounds can be about 0.01: 1 to about 100: 1, is preferably about 0.05 to about 10: 1.

Sulfonyl urea compound and thiazolidine dione compounds that amount is less than the oral antidiabetic of about 150mg can merge in the single tablet with formula I compound.

Formula I compound also can with following drug combination: antihyperglycemic agents such as Regular Insulin or glucagon-like peptide-1 (GLP-1) such as GLP-1 (1-36) acid amides, GLP-1 (7-36) acid amides, GLP-1 (7-37) is (at the United States Patent (USP) 5 of Habener, 614, disclose [incorporating its content into this paper as a reference] in 492) and AC2993 (exenatide) (Amylin) and LY-315902 (N-[3-(1H-imidazol-4 yl)-1-oxopropyl]-26-L-arginine-34-[N6-(1-oxo octyl group)-L-Methionin]-8-37-glucagon-like peptide I (mankind)) (Lilly), it can be by injecting, in the nose, suck or by through skin or contain clothes and put administration.

If exist, then N1,N1-Dimethylbiguanide, sulfonyl urea compound (such as Glyburide, glimepiride, lattice row pyridine, Glipizide, P-607 and gliclazide) and glucosidase inhibitor acarbose or miglitol or Regular Insulin (in injection, the lung, contain clothes or oral) can reach by above-mentioned preparation and use by amount and the administering mode pointed out among Physician ' the sDesk Reference (PDR).

If exist, then the consumption of N1,N1-Dimethylbiguanide or its salt can be every day about 500 to about 2000mg, it can come administration by single dose or broken dose (every day 1 to 4 time).

If exist, then the consumption of thiazolidinediones antidiabetic can be every day about 0.01 to about 2000mg, it can come administration by single dose or broken dose (every day 1 to 4 time).

If exist, then Regular Insulin can use by preparation, amount and the administering mode pointed out among Physician ' the s Desk Reference.

If exist, then the GLP-1 peptide can contain formulation by the oral cavity and comes administration, comes administration or come administration in the parenteral mode by nose, as United States Patent (USP) 5,346,701 (TheraTech), 5,614,492 and 5, described in 631,224, incorporate these patents into this paper as a reference.

Other antidiabetic also can be PPAR α/γ dual agonists, such as AR-HO39242 (for Ge Liezha) (Astra/Zeneca), GW-409544 (Glaxo-Wellcome), KRP297 (5-[(2,4-dioxo thiazolidine-5-yl) methyl]-2-methoxyl group-N-[[4-(trifluoromethyl) phenyl] methyl]-benzamide) (Kyorin Merck) and Murakami et al, " A Novel Insulin Sensitizer Acts As aColigand for Peroxisome Proliferation-Activated Receptor Alpha (PPARalpha) and PPAR gamma.Effect on PPAR alpha Activation on Abnormal LipidMetabolism in Liver of Zucker Fatty Rats ", Diabetes 47, those materials that disclose among the 1841-1847 (1998).

Described antidiabetic can be the SGLT2 inhibitor, and the SGLT2 inhibitor as disclosing in the U. S. application of submitting on October 4th, 2,000 09/679,027 uses wherein said dosage.Preferably in above-mentioned application, be designated as preferred compound.

Described antidiabetic can be the aP2 inhibitor, such as the U. S. application of submitting on September 7th, 1,999 09/391, the aP2 inhibitor that discloses in the U. S. application of submitting in the aP2 inhibitor that discloses in 053 and on March 6th, 2,000 09/519,079 uses wherein said dosage.Preferably in above-mentioned application, be designated as preferred compound.

Described antidiabetic can be the DP4 inhibitor, such as the U. S. application of submitting to February 16 calendar year 2001 09/788,173, WO99/38501, WO99/46272, WO99/67279 (PROBIODRUG), the DP4 inhibitor that discloses among WO99/67278 (PROBIODRUG) and the WO99/61431 (PROBIODRUG), saxagliptin (preferably), Hughes et al, Biochemistry, 38 (36), 11597-11603, (1999) NVP-DPP728A (1-[[[2-[(5-cyanopyridine-2-yl) amino that discloses in] ethyl] amino] ethanoyl]-2-cyano group-(S)-tetramethyleneimine) (Novartis) (preferably), Yamada et al, Bioorg. ﹠amp; The TSL-225 (tryptophyl-1,2,3,4-tetrahydrochysene-isoquinoline 99.9-3-carboxylic acid) and the Ashworth et al that disclose among the Med.Chem.Lett.81537-1540 (1998), Bioorg. ﹠amp; Med.Chem.Lett., Vol.6, the 2-cyanopyrrole alkyl compound and the 4-cyanopyrrole alkyl compound that disclose among the No.22, pp 1163-1166and2745-2748 (1996) use the dosage described in the above document.

Can choose meglitinide compounds with formula I compound of the present invention coupling wantonly and can be repaglinide, nateglinide (Novartis) or KAD 1229 (mitiglinide) (PF/Kissei), wherein repaglinide is preferred.

The weight ratio of formula I compound and meglitinide compounds, PPAR gamma agonist, PPAR α/γ dual agonists, aP2 inhibitor, DP4 inhibitor or SGLT2 inhibitor can be about 0.01: 1 to about 100: 1, is preferably about 0.05 to about 10: 1.

Can choose therapeutical agent with other type of formula I compound coupling wantonly and can be a kind, 2 kinds, 3 kinds or more kinds of in the following antiobesity agent, described antiobesity agent comprises 'beta '3 adrenergic agonists, lipase inhibitor, thrombotonin (and Dopamine HCL) reuptake inhibitor, aP2 inhibitor, thryoid receptor agonist and/or anoretic.

Can choose 'beta '3 adrenergic agonists with the coupling of formula I compound wantonly and can be AJ9677 (rafabegron) (Takeda/Dainippon), L750355 (N-[4-[2-[[(2S)-3-[(6-aminopyridine-3-yl) oxygen base]-the 2-hydroxypropyl] amino] ethyl] phenyl]-4-(1-methylethyl)-benzsulfamide) (Merck) or CP331684 (4-[2-[[2-(6-aminopyridine-3-yl)-2 (R)-hydroxyethyls]-amino] oxyethyl group] phenyl] acetate) (Pfizer) or United States Patent (USP) 5,541,204,5,770,615,5,491,134,5,776,983 and 5,488, other known β 3 agonists that disclose in 064, AJ9677 wherein, L750,355 (N-[4-[2-[[(2S)-3-[(6-aminopyridine-3-yls) oxygen base]-the 2-hydroxypropyl] amino] ethyl] phenyl]-4-(1-methylethyl)-benzsulfamide) and CP331684 be preferred.

The lipase inhibitor that can choose wantonly with the coupling of formula I compound can be orlistat or ATL-962 (Alizyme), and wherein orlistat is preferred.

Thrombotonin (and Dopamine HCL) reuptake inhibitor that can choose wantonly with the coupling of formula I compound can be sibutramine, topiramate (Johnson ﹠amp; Johnson) or axokine (Regeneron), wherein sibutramine and topiramate are preferred.

The thryoid receptor agonist that can choose wantonly with the coupling of formula I compound can be the U.S. Provisional Application of submitting in WO97/21993 (U.Cal SF), WO99/00353 (KaroBio), WO00/039077 (KaroBio) and on February 17th, 2,000 60/183, the ligands for thyroid receptor that discloses in 223, wherein the compound in KaroBio application and the above-mentioned U.S. Provisional Application is preferred.

The anoretic that can choose wantonly with the coupling of formula I compound can be dextroamphetamine, phentermine, Phenylpropanolamine or Mazindol, and wherein dextroamphetamine is preferred.

Above-mentioned various antiobesity agent can use in same formulation with formula I compound or use in different dosage form, and wherein dosage and dosage regimen are as known in the art or described in PDR.

The hypotensive agent (comprising hydragog(ue)) that can comprise ACE inhibitor, angiotensin II receptor antagonists, NEP/ACE inhibitor and calcium channel blocker, beta-adrenergic blocking agent and other type with the hypotensive agent of formula I compound of the present invention coupling.

The angiotensin-convertion enzyme inhibitor that can be used for the application comprises and contains sulfydryl (S-) Bu Fen those angiotensin-convertion enzyme inhibitors; United States Patent (USP) 4 such as people such as proline derivative that replaces such as above-mentioned Ondetti; 046; the proline derivative of any those replacements that disclose in 889 [wherein captopril is 1-[(2S)-3-sulfydryl-2-methylpropionyl]-the L-proline(Pro) is preferred] and the sulfydryl acetyl derivative such as the United States Patent (USP) 4 of the proline(Pro) of replacement; the sulfydryl acetyl derivative [wherein zofenopril is preferred] of the proline(Pro) of any those replacements that disclose in 316,906.

Other example that can be used for the application's the ACE inhibitor that contains sulfydryl comprise the Rentiapril that discloses among the Clin.Exp.Pharmacol.Physiol.10:131 (1983) (fentiapril, Santen) and pivopril and YS980.

Other example that can be used for the application's angiotensin-convertion enzyme inhibitor comprises above-mentioned United States Patent (USP) 4; 374; any those angiotensin-convertion enzyme inhibitors that disclose in 829; wherein N-(1-ethoxy carbonyl-3-phenyl propyl)-L-alanyl-L-proline(Pro) is that enalapril is preferred; United States Patent (USP) 4; 452; amino acid or the imino-acid or the salt of any phosphonate substituted that discloses in 790; (S)-1-[6-amino-2-[[hydroxyl-(4-phenyl butyl) phosphinyl wherein] the oxygen base]-the 1-oxo-hexyl]-L-proline(Pro) or SQ-29852 are preferred; above-mentioned United States Patent (USP) 4; 168; the phosphinyl alkyloyl proline(Pro) compounds that discloses in 267; wherein fosinopril is preferred, United States Patent (USP) 4,337; the proline(Pro) compounds that any phosphinyl alkyloyl that discloses in 201 replaces; with the phosphono aminate (phosphonamidate) that discloses in the above-mentioned United States Patent (USP) 4,432,971.

Other example that can be used for the application's ACE inhibitor comprises the BRL 36,378 of the Beecham that discloses in european patent application 80822 and 60668; The MC-838 of the Chugai that discloses among C.A.102:72588v and the Jap.J.Pharmacol.40:373 (1986); The CGS 14824 of the Ciba-Geigy that discloses in the English Patent 2103614 (3-([1-ethoxy carbonyl-3-phenyl-(1S)-propyl group] amino)-2,3,4,5-tetrahydrochysene-2-oxo-1-(3S)-benzo-aza

The CGS 16,617 that discloses-1-acetic acid hydrochloride) and in the United States Patent (USP) 4,473,575 (3 (S)-[[(1S)-and 5-amino-1-carboxy pentyl] amino]-2,3,4,5-tetrahydrochysene-2-oxo-1H-1-benzo-aza

-1-acetate); The alacepril (cetapril) that discloses among Eur.Therap.Res.39:671 (1986) and the 40:543 (1986) (alacepril (alacepril), Dainippon); The Ramipril (Hoechsst) that discloses among European patent 79-022 and the Curr.Ther.Res.40:74 (1986); The Ru 44570 (Hoechst) that discloses among the Arzneimittelforschung 34:1254 (1985); The Yipingshu (Hoffman-LaRoche) that discloses among the J.J.Cardiovasc.Pharmacol.9:39 (1987); The R 31-2201 (Hoffman-LaRoche) that discloses among the FEBS Lett.165:201 (1984); Lisinopril (Merck); United States Patent (USP) 4,385, the delapril (indalapril) (delapril (delapril)) that discloses in 051; J.Cardiovasc.Pharmacol.5:643,655 (1983) the middle indolaprils (Schering) that disclose; Acta.Pharmacol.Toxicol.59 (Supp.5): the spirapril (Schering) that discloses in 173 (1986); The perindopril (Servier) that discloses among the Eur.J.Clin.Pharmacol.31:519 (1987); United States Patent (USP) 4,344, the quinapril (Warner-Lambert) that discloses in 949; Pharmacologist26:243, the CI925 (Warner-Lambert) that discloses in 266 (1984) ([3S-[2[R (*) R (*)]] 3R (*)]-2-[2-[[1-(oxyethyl group-carbonyl)-3-phenyl propyl] amino]-the 1-oxopropyl]-1,2,3,4-tetrahydrochysene-6,7-dimethoxy-isoquinoline-3-carboxylic acid hydrochloride); And the WY-44221 (Wyeth) that discloses among the J.Med.Chem.26:394 (1983).

Preferred ACE inhibitor is captopril, fosinopril, enalapril, lisinopril, quinapril, benazepril, fentiapril, Ramipril and moexipril.

The NEP/ACE inhibitor also can be used for the application, and this is to suppress active and angiotensin-converting enzyme (ACE) inhibition activity because they have neutral endopeptidase (NEP).The example that is applicable to the application's NEP/ACE inhibitor is included in those NEP/ACE inhibitor that disclose in the following document: United States Patent (USP) 5,362,727,5,366,973,5,225,401,4,722,810,5,223,516,4,749,688, United States Patent (USP) 5,552, and 397, United States Patent (USP) 5,504,080, United States Patent (USP) 5,612, and 359, United States Patent (USP) 5,525,723, european patent application 0599444,0481522,0599444,0595610, european patent application 0534363A2,534396 and 534492 and european patent application 0629627A2.

Preferably in above-mentioned patent/application, be designated as preferred those NEP/ACE inhibitor and dosage thereof, incorporate described United States Patent (USP) into this paper as a reference; Most preferably omapatrilat, BMS189,921 ([S-(R*, R*)]-six hydrogen-6-[(2-sulfydryl-1-oxo-3-phenyl propyl) amino]-2,2-dimethyl-7-oxo-1H-azepine -1-acetate (gemopatrilat)) and CGS 30440.

The angiotensin II receptor antagonists (being also referred to as Angiotensin II antagonist or AII antagonist in this application) that is applicable to the application includes but not limited to irbesartan, losartan, valsartan, Candesartan, telmisartan, Tasosartan or Eprosartan, and wherein irbesartan, losartan or valsartan are preferred.

Preferred oral dosage form (such as tablet or the capsule) ACE inhibitor that is contained or the amount of AII antagonist can be about 0.1 to about 500mg, are preferably about 5 to about 200mg, and more preferably about 10 to about 150mg.

For administered parenterally, the consumption of ACE inhibitor, Angiotensin II antagonist or NEP/ACE inhibitor can be about 0.005mg/kg to about 10mg/kg, and is preferably about 0.01mg/kg to about 1mg/kg.

When medicine is treated intravenous administration, medicine can be formulated in conventional vehicle such as distilled water, salt solution, Ringer's solution or other the conventional carrier.

It should be understood that the preferred dose of other antihypertensive drug that ACE inhibitor and AII antagonist and the application disclose is pointed in can Physician ' the s Desk Reference (PDR) as latest edition.

Other example that is applicable to the application's preferred hypotensive agent comprises omapatrilat

Amlodipine besylate

PRAZOSINI HYDROCHLORIDE

Verapamil, nifedipine, nadolol, Odizem, felodipine, nisoldipine, Isrodipine, nicardipine, atenolol USP 23, carvedilol, sotalol, terazosin, Doxazosin, Proprasylyte and Tenso-Timelets

Can comprise hydrochlorothiazide, torasemide, Furosemide, spironolactone and indapamide with the hydragog(ue) of formula I compound coupling.

Can comprise acetylsalicylic acid, clopidogrel, ticlopidine, Dipyridamole, ReoPro, Tirofiban, eptifibatide, anagrelide and Ifetroban with the anti-platelet agents of formula I compound of the present invention coupling, wherein clopidogrel and acetylsalicylic acid are preferred.

Described antiplatelet drug can use by the amount of pointing out among the PDR.Ifetroban can be by United States Patent (USP) 5,100, and the amount of pointing out in 889 is used.

Be suitable in this application comprising that with the osteoporosis agent of formula I compound of the present invention coupling parathyroid hormone or diphosphonate compounds are [such as MK-217 (alendronate)

].

The using dosage of said medicine can be as pointed among Physician ' the s Desk Reference.

Medicine

Pharmaceutical composition of the present invention comprises and can give the experimenter and not destroy pharmaceutically acceptable carrier, auxiliary material or the vehicle of The compounds of this invention pharmacological activity with The compounds of this invention.The pharmaceutically acceptable carrier that can in pharmaceutical composition of the present invention, use, auxiliary material and vehicle include but not limited to ion-exchanger, aluminum oxide, aluminum stearate, Yelkin TTS, self-emulsifying drug delivery systems (SEDDS) is such as succsinic acid D-alpha-tocopherol cetomacrogol 1000 ester, the tensio-active agent that in pharmaceutical dosage form, uses such as Tween or other similar polymkeric substance delivery matrices, serum protein are such as human serum albumin, buffer substance is such as phosphoric acid salt, glycine, Sorbic Acid, potassium sorbate, the partial glyceride mixture of saturated vegetable fatty acid, water, salt or ionogen are such as protamine sulfate, Sodium phosphate dibasic, potassium hydrogen phosphate, sodium-chlor, zinc salt, colloid silica, Magnesium Trisilicate, Polyvinylpyrolidone (PVP), based on cellulosic material, polyoxyethylene glycol, Xylo-Mucine, polyacrylic ester, wax, polyethylene-polyoxypropylene block polymer, polyoxyethylene glycol and lanolin.Also can use cyclodextrin such as α-, β-and γ-Huan Hujing or chemically modified derivative such as hydroxyalkyl cyclodextrin (comprising 2-and 3-hydroxypropyl-cyclodextrin) or other soluble derivative to promote sending of conditioning agent of the present invention.

The present composition can contain following other therapeutical agent, and can for example prepare according to known those technology of field of pharmaceutical preparations by the medicated premix (for example vehicle, tackiness agent, sanitas, stablizer, correctives etc.) that uses conventional solid or liquid vehicle or thinner and type to be suitable for required mode of administration.

The compounds of this invention can come administration by any suitable method by the dosage unit preparations form that contains nontoxic pharmaceutically acceptable vehicle or thinner, such as coming oral administration with the form of tablet, capsule, granule or powder agent; Sublingual administration; Orally administering; Such as coming administered parenterally by subcutaneous, intravenously, intramuscular or breastbone inner injection or the infusion techniques form of sterile injectable water-based or non-aqueous solution agent or suspensoid (for example with); Such as coming nose administration by sucking spraying; Such as coming topical with the form of ointment or ointment; Or such as coming the per rectum administration with the form of suppository.The compounds of this invention can be for example to be suitable for discharging immediately or prolonging the form that discharges coming administration.Discharge immediately or prolong and discharge and followingly to realize: use the suitable drug composition that contains The compounds of this invention, or, use such as subcutaneous implant or the such device of osmotic pump particularly prolonging under the situation about discharging.The compounds of this invention also can come administration by liposome.

The exemplary composition that is used for oral administration comprises following preparation: suspensoid, and it can contain the Microcrystalline Cellulose that for example is used to give volume (bulk), as the Lalgine of suspending agent or sodium alginate, as methylcellulose gum and the sweetener known in the art or the correctives of thickening material; Release tablet immediately, it can contain for example Microcrystalline Cellulose, Lin Suanergai, starch, Magnesium Stearate and/or lactose and/or other vehicle known in the art, tackiness agent, expanding material (extender), disintegrating agent, thinner and lubricant.The compounds of this invention also can and/or contain the clothes administration by sublingual administration and come via oral delivery.Molded tablet, compressed tablets or lyophilize tablet are spendable exemplary form.Exemplary compositions comprises one or more The compounds of this invention and quick stripping thinner [such as N.F,USP MANNITOL, lactose, sucrose and/or cyclodextrin] those compositions formulated together.Such preparation also can comprise high molecular vehicle such as Mierocrystalline cellulose (Avicel) or polyoxyethylene glycol (PEG).Such preparation also can comprise vehicle such as hydroxypropylcellulose (HPC), Vltra tears (HPMC), Xylo-Mucine (SCMC) and/or the copolymer-maleic anhydride (for example Gantrez) of auxiliary mucosal adhesive and be used for material such as polyacrylic acid (ester) multipolymer (for example Carbopol 934) of sustained release.Also can add lubricant, glidant, correctives, tinting material and stablizer so that processing and use.

The exemplary composition that is used for the nose aerosol or is used for inhalation is included in the solution of salt solution, and it can contain for example benzylalcohol or other suitable sanitas, improve absorption enhancer and/or other solubilizing agent known in the art or the dispersion agent of bioavailability.

The exemplary composition that is used for administered parenterally comprises injection solution agent or suspensoid, its can contain for example suitable nontoxic parenteral acceptable diluent or solvent (such as N.F,USP MANNITOL, 1,3 butylene glycol, water, Ringer's solution (Ringer ' s solution), etc. open sodium chloride solution) or other suitable dispersion agent or wetting agent and suspending agent (comprising synthetic monoglyceride or triglyceride and lipid acid (comprising oleic acid)).That term used in this application " parenteral " comprises is subcutaneous, in the intracutaneous, intravenously, intramuscular, intraarticular, intra-arterial, synovial membrane, in the breastbone, in the sheath, intralesional and intracranial injection or infusion techniques.

The exemplary composition that is used for rectal administration comprises suppository, it can contain for example suitable nonirritating vehicle such as cocoa ester, synthetic glyceryl ester or polyoxyethylene glycol, described suppository is solid-state at normal temperature, but in rectal tract liquefaction and/or dissolving to discharge medicine.

The exemplary composition that is used for topical comprises topical carrier such as Plastibase (with the mineral oil of polyethylene gelling).

Those skilled in the art can determine the significant quantity of The compounds of this invention, and the exemplary dose that is used to be grown up be about 0.1 to the 500mg active compound of every kg body weight every day or every day 0.5 to 2000mg, it can come administration by the form of single dose or the broken dose that separates [such as every day 1 to 5 time].It should be understood that, the given dose level that is used for any concrete experimenter can be different with administration frequency and will depend on multiple factor that these factors comprise the metabolic stability of the activity of used specific compound, described compound and act on the seriousness of duration, experimenter's species, age, body weight, general health, sex and diet, mode of administration and number of times, discharge rate, drug regimen and concrete illness.The preferred experimenter who receives treatment comprises animal, most preferably is mammalian species such as human and domestic animal such as dog, cat etc.

The typical capsule that is used for oral administration contains formula I compound (250mg), lactose (75mg) and Magnesium Stearate (15mg).Make described mixture by 60 eye mesh screens and be filled in No. 1 capsule.

Typical injection is prepared as follows: under aseptic condition 250mg formula I compound is placed bottle, freeze-drying and sealing under aseptic condition.When using, the content in the bottle is mixed with 2mL physiological saline with preparation injectable goods.

Formula I compound of the present invention is a glucocorticoid receptor modulator, this is as follows: they can combine with glucocorticoid receptor in measuring at GR, or as shown, they can suppress the AP-1 activity in the cell trans-repression is measured, and as shown, they do not cause any trans-activation or cause minimum trans-activation in the cell trans-repression is measured.

In following at least a mensuration, tested The compounds of this invention (comprising the compound described in the embodiment), and these compounds have, and glucocorticoid receptor (GR)/dexamethasone (Dex) suppresses active (suppressing active＞25% when concentration is 10 μ M) and/or AP-1 suppresses active (EC ₅₀Less than 15 μ M).

The U. S. application 10/621,807 that identical and/or similar mensuration was submitted to referring on July 17th, 2003 is incorporated its full content into this paper as a reference.

GR is in conjunction with mensuration

Glucocorticoid receptor is in conjunction with measuring (I)

For the affinity of evaluation test compound, use to be purchased test kit (Glucocorticoid Receptor Competitor Assay Kit, Invitrogen Part # 2893) to the human glucocorticoid receptor.Briefly, mix under purified people's recombinant full-lenght glucocorticoid receptor (2nM) and the situation that has or do not exist test compounds through fluorescently-labeled glucocorticosteroid (1nM Fluormone GS Red).After the room temperature lucifuge is hatched 2 hours, the fluorescence polarization of measure sample (FP).On behalf of background fluorescence or 100%, the FP of the mixture of acceptor, fluorescent probe (being Fluormone GS Red) and 5 μ M dexamethasone suppress, and is 100% combination with the FP of the mixture (but having vehicle) of no dexamethasone.Inhibition percentage ratio with test compounds compares and is expressed as the active percentage ratio of relative combination with the sample that contains 5 μ M dexamethasone then, wherein dexamethasone be 100% and unrestraint be 0%.In the concentration range of 8.5E-05 μ M to 5 μ M, test compounds is analyzed.

Glucocorticoid receptor is in conjunction with measuring (II)

In order to measure the combination of compound on glucocorticoid receptor, use be purchased test kit (Glucocorticoid Receptor Competitor Assay Kit, PanVera Co., Madison, WI, P2816).Briefly, make to contain under the lysate of recombinant expressed people's total length glucocorticoid receptor and the situation that has or do not exist test compounds through fluorescently-labeled glucocorticosteroid (1nM Fluormone GS1) and mix.After room temperature is carried out 1 hour, the fluorescence polarization of measure sample (FP).On behalf of background fluorescence or 100%, the FP of the mixture of acceptor, fluorescent probe (being Fluormone GS1) and 1mM dexamethasone suppress, and is 100% combination with the FP of the mixture of no dexamethasone.Inhibition percentage ratio with test molecule compares and is expressed as the active percentage ratio of relative combination with the sample that contains the 1mM dexamethasone then, wherein dexamethasone be 100% and unrestraint be 0%.In the concentration range of 2.4nM to 40 μ M, test molecule is analyzed.

Site I at any NHR (nuclear hormone receptor) similarly carries out in conjunction with measuring with above-mentioned.Suitable lysate or purified NHR are as the source of HR.Fluorescent probe and unlabelled competitor are suitable for specific NHR, and promptly fluorescent probe and unlabelled competitor are the parts of specific NHR.

The cell trans-repression is measured

In order to measure the ability of test molecule to suppressing by AP-1 inductive transcriptional activity, the inventor uses the A549 cell with following plasmid stable transfection, described plasmid contains 7 * AP-1 DNA binding site (pAP-1-Luc plasmid before luciferase genes, Stratagene Co.La Jolla, CA).(phorbol myristic acid PMA) activates 7 hours to cell under the situation that has or do not exist test molecule with 10ng/ml phorbol tetradecanoic acid.After 7 hours, add luciferase reagent to measure the luciferase activity in the cell.After cell is hatched 10 minutes, in the TopCount luminescent counter, measure luminous luciferase reagent.Will to AP-1 active prevent be calculated to be with respect to PMA separately due to the reduction percentage ratio of signal.In the concentration range of 0.1nM to 40 μ M, test molecule is analyzed.Use the typical curve approximating method such as Excel match (Microsoft Co.), determine EC50 thus.EC50 is such test molecule concentration, prevents when described concentration for maximum and transcribes 50% of inhibition, that is to say to make the active reduction by 50% of AP-1.

In measuring, the cell trans-repression also can use other acceptor and clone.Similarly measure, wherein measuring N F-kB activity.Use contains plasmid such as the pNF-κ B-Luc (Stratagene, LaJolla CA) of NF-κ B DNA binding site, and uses PMA or another kind of stimulator such as TNF-α or lipopolysaccharides with activation NF-kB pathway.Can use K. with Yamamoto, et al., J.Biol.Chem., Dec 29; 270 (52): NF-κ B similar described in the 31315-20 (1995) measures.

Above-mentioned cell trans-repression is measured and be can be used for the trans-repression that is caused by any NHR is measured.It will be understood by those skilled in the art that mensuration may need to add such as the such component of stimulator (for example PMA, lipopolysaccharides, TNF-α etc.), described component will cause transcribing by AP-1 or NF-κ B mediation.

In addition, the trans-repression by the AR mediation can pass through Palvimo JJ, et al.J.Biol.Chem., Sep27; 271 (39): the mensuration described in the 24151-6 (1996) is measured, and can pass through Kalkhoven E. by the trans-repression of PR mediation, et al.J.Biol.Chem., and Mar 15; 271 (11): the mensuration described in the 6217-24 (1996) is measured.

In following preparation and embodiment part, provided the embodiment of the The compounds of this invention for preparing by the method described in the general approach.The embodiment compound prepares with the form of racemic mixture usually.The embodiment of chiral purity can prepare by technology well known by persons skilled in the art.For example, the compound of chiral purity can be prepared as follows: by chirality mutually preparation property HPLC racemic product is separated.Selectively, the embodiment compound can prepare to obtain being enriched with the product of enantiomer by known method.These methods include but not limited to the auxiliary functional group of chirality (it is used for the diastereomer selectivity that transforms is controlled) is incorporated into racemic intermediate to obtain being enriched with the product of enantiomer after the fracture of the auxiliary functional group of chirality.

Abbreviation

Abbreviation below in this specification sheets and following preparation and embodiment, using:

The Ph=phenyl

The Bn=benzyl

The iBu=isobutyl-

The t-Bu=tertiary butyl

The Me=methyl

The Et=ethyl

The ACN=acetonitrile

The TMS=trimethyl silyl

TMSN ₃=trimethyl silyl nitrine

The TBS=t-butyldimethylsilyl

FMOC=fluorenyl methoxy carbonyl

The Boc=tert-butoxycarbonyl

Cbz=benzyl oxygen base carbonyl

The THF=tetrahydrofuran (THF)

Et ₂The O=ether

The hex=hexane

The EtOAc=ethyl acetate

The DMF=dimethyl formamide

MeOH=methyl alcohol

The Et=ethyl

EtOH=ethanol

I-PrOH or iPr=Virahol

The DMSO=dimethyl sulfoxide (DMSO)

DME=1,2 glycol dimethyl ethers

DCE=1, the 2-ethylene dichloride

HMPA=hexamethylphosphoramide (hexamethylphosphoric triamide)

HOAc or AcOH=acetate

The TFA=trifluoroacetic acid

The TFAA=trifluoroacetic anhydride

I-Pr ₂The NEt=diisopropyl ethyl amine

Et ₃The N=triethylamine

The NMM=N-methylmorpholine

The DMAP=4-dimethyl aminopyridine

NaBH ₄=sodium borohydride

NaBH (OAc) ₃=sodium triacetoxy borohydride

The DIBALH=diisobutyl aluminium hydride

LAH or LiAlH ₄=lithium aluminium hydride

The n-BuLi=n-Butyl Lithium

The LDA=lithium diisopropylamine

Pd/C=palladium/carbon

PtO ₂=platinum dioxide

KOH=potassium hydroxide

NaOH=sodium hydroxide

The LiOH=lithium hydroxide

K ₂CO ₃=salt of wormwood

NaHCO ₃=sodium bicarbonate

DBU=1,8-diazabicylo [5.4.0] 11 carbon-7-alkene

EDC (or EDC.HCl) or EDCI (or EDCI.HCl) or EDAC=3-ethyl-3 '-(dimethylamino) propyl group-carbodiimide hydrochloride (or 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride)

HOBT or HOBT.H ₂The O=1-hydroxy benzotriazole hydrate

HOAT=1-hydroxyl-7-azepine benzotriazole

Bop reagent=benzotriazole-1-base oxygen base-three (dimethylamino) Phosphonium hexafluorophosphate

NaN (TMS) ₂=hexamethyl dimethyl silanyl sodium amide or two (trimethyl silyl) sodium amide

Ph ₃The P=triphenylphosphine

Pd (OAc) ₂=acid chloride

(Ph ₃P) ₄The Pd=tetrakis triphenylphosphine palladium

The DEAD=diethylazodicarboxylate

The DIAD=diisopropyl azo-2-carboxylic acid

The Cbz-Cl=chloroformic acid benzyl ester

The CAN=ceric ammonium nitrate

The SAX=strong anion exchanger

The SCX=strong cation exchanger

The Ar=argon gas

N ₂=nitrogen

Min=minute

H or hr=hour

The L=liter

The mL=milliliter

μ L=microlitre

The g=gram

The mg=milligram

The mol=mole

The mmol=mmole

The meq=milliequivalent

Rt or RT=room temperature

Sat or sat ' d=are saturated

Aq.=is aqueous

The TLC=thin-layer chromatography

The HPLC=high performance liquid chromatography

Reversed-phase HPLC=RPLC [using YMC ODS S5 post and binary eluent (solvent orange 2 A/solvent B)]

Solvent orange 2 A=10%MeOH-90%H ₂O-0.1%TFA

Solvent B=90%MeOH-10%H ₂O-0.1%TFA; Or

Solvent orange 2 A=the contain H of 0.1%TFA ₂O

Solvent B=contains the ACN of 0.1%TFA

LC/MS=high performance liquid chromatography/mass spectrum

MS or Mass Spec=mass spectrum

The NMR=nucleus magnetic resonance

The NMR spectroscopic data: s=is unimodal; The d=doublet; The m=multiplet; The br=broad peak; The t=triplet

The mp=fusing point

Embodiment

Following embodiment shows the embodiment and the raw material of The compounds of this invention, but not is intended to limit the scope of claims.

Analytical HPLC method

Method A:

Last the linear gradient of 4 minutes 0 to 100% solvent B, kept 1 minute at 100%B.

Carry out ultraviolet visualization at 220nm

Chromatographic column: YMC CombiScreen ODS-A S5 4.6 * 50mm

Flow velocity: 4mL/min

Solvent orange 2 A: 0.2% phosphoric acid-90% water-10% methyl alcohol

Solvent B:0.2% phosphoric acid-90% methyl alcohol-10% water

Method B:

Carry out ultraviolet visualization at 220nm

Chromatographic column: YMC S5 ODS-A 4.5 * 50mm

Flow velocity: 4mL/min

Solvent orange 2 A: 0.2% phosphoric acid-90% water-10% methyl alcohol

Solvent B:0.2% phosphoric acid-90% methyl alcohol-10% water

Embodiment 1

4-(5-(1,1-dimethyl-2-oxo-2-(1,3,4-thiadiazoles-2-base is amino) ethyl)-5H-pyrido [4 ', 3 ': 5,6] pyrans is [2,3-b] pyridine-2-yl also)-N, the N-dimethyl benzamide

Step 1

(36.3g, (10.35g is 65.7mmol) in the solution in DMSO (50mL) 263mmol) to be added to 3-chloropyridine-4-formic acid with salt of wormwood.After 30 minutes, and adding MeI (8.22mL, 131mmol).Mixture stirring at room 2 hours, is used saturated NH ₄Cl (300mL) and water (200mL) cancellation, and with EtOAc (3 * 200mL) extraction.(2 * 50mL) wash the extract that merges, dry (MgSO with salt solution ₄) and concentrate.Carry out purifying (with 10-30% ethyl acetate/hexane wash-out) with silica gel chromatography, obtain 3-chloropyridine-4-methyl-formiate, it is colourless liquid (6.275g, 56% yield).MS (ES+) m/z:172 (M+H); LC retention time: 2.45 minutes (analytical HPLC method A).

Step 2

(16.79mL, (6.23mL is 43.7mmol) in the solution in THF (150mL) 42.0mmol) dropwise to be added to diisopropylamine at-78 ℃ with the hexane solution of 2.5M BuLi (butyllithium).Mixture was stirred 15 minutes and is cooled to-78 ℃ at 0 ℃.Dropwise add acetonitrile (2.192mL, 42.0mmol).Solution gradually becomes oyster white.After 1 hour, dropwise add 3-chloropyridine-4-methyl-formiate (3.00g, 17.48mmol) solution in THF (10mL)-78 ℃ of maintenances.Flask also adds with THF (2mL) drip washing.-78 ℃ keep 1 hour after, mixture is with salt solution (200mL) cancellation and to be acidified to pH be about 1.Vacuum-evaporation THF.(3 * 100mL) extract the water-based residue with EtOAc.The extract that merges washs with salt solution (50mL), dry (MgSO ₄) and concentrate, obtaining impure 3-(3-chloropyridine-4-yl)-3-oxypropionitrile, it is tawny solid (3.12g, 81% purity, 80% yield).MS (ES+) m/z:181 (M+H); LC retention time: 1.90 minutes (analytical HPLC method A).

Step 3

(25g, 140mmol) and N, the mixture heating up of dinethylformamide dimethyl acetal (100mL) is to refluxing and kept 2 days, dilutes and is cooled to 0 ℃ with MeOH (100mL) with 4-acetylbenzoic acid methyl esters.Filter the collecting precipitation thing and with the MeOH washing, obtain (E)-4-(3-(dimethylamino) acryl) methyl benzoate, it is brown solid (27.65g, 84% yield).MS (ES+) m/z:234 (M+H); LC retention time: 2.91 minutes (analytical HPLC method A).

Step 4

With (E)-4-(3-(dimethylamino) acryl) methyl benzoate (1.85g; 7.93mmol), 3-(3-chloropyridine-4-yl)-3-oxypropionitrile (2.005g; 11.10mmol), acetate (2.270mL; 39.7mmol) and the mixture heating up to 140 of DMF (20mL) ℃ and keeping 62 hours, be cooled to room temperature and with MeOH (20mL) dilution.Filter the collecting precipitation thing and use the MeOH washed twice, obtain needed diaza folder oxygen anthrone, it is brown ceramic powder (932.9mg, 35% yield).MS (ES+) m/z:333 (M+H); LC retention time: 4.02 minutes (analytical HPLC method A).

Step 5

(1.062g, (932.9mg is 2.81mmol) at MeOH (50mL) and CH 28.1mmol) to be added to the product that is obtained by step 4 at 0 ℃ with sodium borohydride ₂Cl ₂In the suspension (50mL).0 ℃ keep 3 hours after, the saturated NH of mixture ₄Cl (100mL) and water (100mL) cancellation.The vacuum-evaporation organic solvent.Filter collecting precipitation thing and water (2 *) and MeOH washing, obtain needed diaza folder oxygen anthranol, it is pale solid (759.3mg, 81% yield).MS (ES+) m/z:335 (M+H); LC retention time: 3.20 minutes (analytical HPLC method A).

Step 6

With DMAP (963mg, 7.88mmol) and Ac ₂(0.279mL, (659mg is 1.971mmol) at CH 2.96mmol) to be added to the alcohol that is obtained by step 5 at 0 ℃ for O (diacetyl oxide) ₂Cl ₂In the suspension (25mL).Mixture gradually becomes homogeneous solution.After room temperature keeps 30 minutes, mixture salt solution (50mL) cancellation.Separate two-phase and water CH ₂Cl ₂(2 * 25mL) extractions.With the dichloromethane extract drying (MgSO that merges ₄) and concentrate.Carry out purifying (with 30-65%EtOAc/ hexane wash-out) with silica gel chromatography, obtain needed acetic ester product, it is white solid (686.2mg, 92% yield).MS (ES+) m/z:377 (M+H); LC retention time: 3.88 minutes (analytical HPLC method A).

Step 7

(0.686g is 1.823mmol) at CH to the acetic ester that is obtained by step 6 at 0 ℃ ₂Cl ₂The CH that adds 1M titanium tetrachloride (IV) in the solution (50mL) ₂Cl ₂Solution (3.65mL, 3.65mmol).Gained tawny suspension was stirred 5 minutes at 0 ℃.Add dimethyl ketene contract methyl alcohol trimethyl silyl alcohol (methyl trimethylsilyl dimethylketene acetal) (1.148mL, 5.649mmol).Mixture was stirred 1 hour at 0 ℃, use saturated NaHCO ₃(50mL) cancellation, stirring is spent the night and is filtered through Celite pad., Celite pad CH ₂Cl ₂Drip washing.Separate two-phase and water CH ₂Cl ₂(2 * 50mL) extractions.With the organic extract drying (MgSO that merges ₄) and concentrate.Carry out purifying (with 30-70%EtOAc/ hexane wash-out) with silica gel chromatography, obtain needed product, it is white solid (350mg, 46% yield).MS (ES+) m/z:419 (M+H); LC retention time: 3.83 minutes (analytical HPLC method A).

Step 8

(20mL, (350mg is 0.836mmol) at MeOH (50mL), THF (50mL) and CH 20.00mmol) to be added to the product that is obtained by step 7 with the 1N NaOH aqueous solution ₂Cl ₂In the solution (25mL).After room temperature keeps 4 hours, mixture 1N HCl (21mL) cancellation.The vacuum-evaporation organic solvent.Filtration collecting precipitation thing also washes with water, obtains needed acid, and it is white powder (268.3mg, 79% yield).MS (ES+) m/z:405 (M+H); LC retention time: 3.45 minutes (analytical HPLC method A).

Step 9

With Xu Nixi (Hunig ' s) alkali (0.429mL, 2.458mmol) be added to the acid (165.7mg that obtains by step 8,0.410mmol), I-hydroxybenzotriazole hydrate (125mg, 0.819mmol) and N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride (157mg is 0.819mmol) in the suspension in DMF (5mL).After room temperature keeps 30 minutes, and the THF solution of adding 2M dimethyl amine (0.615mL, 1.229mmol).After 3 hours, add dimethyl amine (1mL) again.After 24 hours, mixture is concentrated altogether.(YMC ODS S530 * 100mm chromatographic column, gradient is 45 to 65% solvent B) carries out purifying with reversed-phase HPLC, obtains needed product, and it is a thickness oily matter, is estimated as two-tfa salt (134.5mg, 50% yield).MS (ES+) m/z:432 (M+H); LC retention time: 3.15 minutes (analytical HPLC method A).Also be recovered to unreacted raw material (63.0mg).

Step 10

(400mg, (134.5mg is 0.204mmol) in the solution in DMF (5mL) 4.08mmo1) to be added to the product that is obtained by step 9 with 2-rosickyite sodium alkoxide.Mixture was stirred 1 hour at 50 ℃,, use saturated NH with 1NHCl (3.84mL) cancellation ₄Cl (30mL) dilution, being adjusted to pH with 1N NaOH is 7-8, and uses CHCl ₃(6 * 25mL) extractions.With the extract drying (MgSO that merges ₄) and concentrate, obtaining needed acid, it is little yellow solid (84.4mg, 99% yield).MS (ES+) m/z:418 (M+H); LC retention time: 2.91 minutes (analytical HPLC method A).

Step 11

With O-(7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethyl-urea hexafluorophosphate (52.6mg, 0.138mmol) and (0.081mL, (32.1mg is 0.077mmol) in the solution in DMF (2mL) 0.461mmol) to be added to the acid that is obtained by step 10 to be permitted the uncommon alkali of Buddhist nun.With brown solution stirring at room 30 minutes.Add 1,3, and 4-thiadiazoles-2-amine (23.33mg, 0.231mmol).Mixture is spent the night 80 ℃ of stirrings.80 ℃ keep 20 hours after, mixture concentrated and carry out purifying with reversed-phase HPLC (Sunfire S1030 * 250mm chromatographic column, gradient is 45 to 65% solvent B), obtain embodiment 1, be estimated as two-tfa salt (26.6mg, 48% yield). ¹H NMR (400MHz, the δ ppm 9.11 of methyl alcohol-d4) (1H, s), 8.81 (1H, s), 8.48 (1H, d, J=4.03Hz), 8.13 (2H, d, J=8.31Hz), 7.82 (2H, s), 7.69 (1H, d, J=5.54Hz), 7.54 (2H, d, J=8.31Hz), 4.85 (1H, s), 3.12 (3H, s), 3.03 (3H, s), 1.25 (3H, s), 1.24 (3H, s); MS (ES+) m/z:501 (M+H); LC retention time: 3.08 minutes (analytical HPLC method A).

Embodiment 2

2-methyl-2-(2-(4-(morpholine-4-base carbonyl) phenyl)-5H-pyrido [4 ', 3 ': 5,6] pyrans is [2,3-b] pyridine-5-yl also)-N-(1,3,4-thiadiazoles-2-yl) propionic acid amide

Step 1

With I-hydroxybenzotriazole hydrate (0.048g, 0.312mmol), N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride (0.060g, 0.312mmol) and permitted the uncommon alkali (0.163mL of Buddhist nun, 0.936mmol) (0.063g is 0.156mmol) at DMF (5mL) and CH to be added to the acid that is obtained by embodiment 1 step 8 in room temperature ₂Cl ₂In the solution (10mL).After 5 minutes, and the adding morpholine (0.054mL, 0.624mmol).Mixture was stirred 13 hours, use saturated NH ₄Cl (25mL) cancellation is also used CH ₂Cl ₂(3 * 10mL) extractions.With the extract drying (MgSO that merges ₄) and concentrate, obtaining needed product, it is little yellow solid.Thick material need not purifying and promptly is used for next reaction.MS (ES+) m/z:474 (M+H); LC retention time: 3.13 minutes (analytical HPLC method A).

Step 2

(10mL 10.00mmol) is added in the suspension of crude product in MeOH (10mL) and THF (10mL) that is obtained by step 1 with 1N NaOH solution.With mixture heating up to refluxing and keeping 1 hour.HPLC demonstrates about 1: 1 mixture of following substances: needed ester hydrolysate and the monoprotic acid that is obtained by the selectivity amide hydrolysis.In addition, there be the small peak relevant with dicarboxylic acid product (main peak of respectively doing for oneself about 25%) with unreacted raw material.The vacuum-evaporation organic solvent.To be acidified to pH be about 2 to the water-based residue and use CH with 1N HCl ₂Cl ₂(3 * 15mL) extractions.Still have product at aqueous phase.Water solid NH ₄Cl saturated and with EtOAc (3 * 15mL) extraction.With the extract drying (MgSO that merges ₄) and concentrate, obtaining pale solid, it need not purifying and promptly is used for next reaction.

Step 3

With I-hydroxybenzotriazole hydrate (96mg, 0.624mmol), N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride (120mg, 0.624mmol) and (0.327mL 1.872mmol) is added in the solution of thick acid in DMF (5mL) that is obtained by step 2 in room temperature to be permitted the uncommon alkali of Buddhist nun.After 5 minutes, add 1,3, (95mg is 0.936mmol) and with mixture heating up to 70 ℃ and kept 3 hours for 4-thiadiazoles-2-amine.Vacuum-evaporation DMF.The saturated NH of residue ₄Cl (25mL) dilutes and uses CH ₂Cl ₂(3 * 10mL) extractions.With the extract drying (MgSO that merges ₄) and concentrate.Carry out purifying with reversed-phase HPLC (Sunfire S10 30 * 250mm chromatographic column, gradient are 50 to 75% solvent B), obtain embodiment 2, be estimated as two-tfa salt (18.1mg, three step yields are 15%). ¹HNMR (400MHz, methyl alcohol-d ₄) δ ppm 8.99 (1H, s), 8.63 (1H, s), 8.32 (1H, s), 8.02-8.06 (2H, m), 7.70 (2H, s), 7.32-7.54 (3H, m), 4.70 (1H, s), 3.58-3.74 (4H, m), 3.47-3.58 (2H, m), 3.31-3.44 (2H, m), 1.13 (3H, s), 1.11 (3H, s); MS (ES+) m/z:543 (M+H); LC retention time: 3.07 minutes (analytical HPLC method A).

Embodiment 3

4-(5-(1,1-dimethyl-2-oxo-2-(1,3,4-thiadiazoles-2-base is amino) ethyl)-5H-pyrido [3 ', 2 ': 5,6] pyrans is [2,3-b] pyridine-2-yl also)-N, the N-dimethyl benzamide

Step 1

(339mL, (81mL is 566mmol) in the solution in THF (600mL) 543mmol) to be added to diisopropylamine at-78 ℃ with the hexane solution of 1.6M BuLi.Mixture was stirred 30 minutes and is cooled to-78 ℃ at 0 ℃.Dropwise add acetonitrile (28.4mL, 543mmol).After 1 hour, dropwise add 2-chloropyridine-3-ethyl formate (42g, 226mmol) solution in THF (200mL)-78 ℃ of maintenances.The gained mixture was stirred 1 hour at-78 ℃, and with salt solution (200mL) cancellation, being warming up to room temperature and being adjusted to pH with 1NHCl is 1-2.Separate two-phase.(2 * 500mL) extract water layer with ethyl acetate.The organic phase that merges is washed with salt solution (400mL), dry (MgSO ₄) and concentrate.With residue heating for dissolving and be cooled to room temperature in ethyl acetate (200mL).Filter and collect brown solid, obtain needed product (26.6g, 65% yield).MS (ES+) m/z:181 (M+H); LC retention time: 1.69 minutes (analytical HPLC method A).

Step 2

With acetate (1.838mL; 32.1mmol) be added to (E)-4-(3-(dimethylamino) acryl) methyl benzoate (1.498g; 6.42mmol) and 3-(2-chloropyridine-3-yl)-3-oxypropionitrile (1.52g is 8.42mmol) in the mixture in N,N-dimethylacetamide (20mL).Mixture was stirred 6 hours at 120 ℃, be cooled to room temperature, stirred 30 minutes with MeOH (20mL) dilution and at 0 ℃.Yellow solid is filtered and wash, obtain needed product (1.64g, 77% yield) with cold MeOH.MS (ES+) m/z:333 (M+H); LC retention time: 3.90 minutes (analytical HPLC method A).

Step 3

(7.29g, (12.8g is 38.5mmol) in the suspension in MeOH (400mL) and methylene dichloride (100mL) 193mmol) to be added to the ketone that is obtained by step 2 at 0 ℃ with aliquot with sodium borohydride.Mixture was stirred 2 hours at 0 ℃, also used saturated NH in 3 hours in stirring at room ₄Cl (100mL) and H ₂O (100mL) cancellation.Stir after 20 minutes the vacuum-evaporation organic solvent.Aqueous suspension is filtered and brown solid H ₂O, cold methanol and washed with dichloromethane and vacuum-drying obtain needed product (11.7g, 91% yield).MS (ES+) m/z:335 (M+H); LC retention time: 3.40 minutes (analytical HPLC method A).

Step 4

(11.7g is 35.0mmol) at CH to the alcohol that is obtained by step 3 at 0 ℃ ₂Cl ₂The CH that adds 1M titanium tetrachloride (IV) in the suspension (300mL) ₂Cl ₂Solution (52.5mL, 52.5mmol).Gained tawny suspension was stirred 5 minutes.Add dimethyl ketene contract methyl alcohol trimethyl silyl alcohol (21.33mL, 105mmol).Mixture was stirred 1 hour at 0 ℃, and use saturated NaHCO ₃(100mL) cancellation.Separate organic layer and water CH ₂Cl ₂(2 * 100mL) extractions.The organic layer that merges washs with salt solution (100mL), dry (MgSO ₄) and be concentrated into small volume.In concentration process, faint yellow solid is smashed to pieces, and filtered and collect and vacuum-drying, obtain needed product (9.7g, 66% yield).MS (ES+) m/z:419 (M+H); LC retention time: 3.36 minutes (analytical HPLC method A).

Step 5

(30mL, (689mg is 1.647mmol) in the suspension in THF (30mL) and MeOH (30mL) 30.0mmol) to be added to the product that is obtained by step 4 with the 1N NaOH aqueous solution.After being heated to backflow, mixture becomes yellow solution.Reflux after 4.5 hours the vacuum-evaporation organic solvent.The water-based residue is cooled to 0 ℃, and to be acidified to pH by slow adding 1N HCl be about 3.Mixture is filtered.(2 * 25mL) washing and vacuum-dryings obtain needed product (601mg, 93% yield) to the solid water.MS (ES+) m/z:391 (M+H); LC retention time: 3.45 minutes (analytical HPLC method A).

Step 6

With O-(7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethyl-urea hexafluorophosphate (1.086g, 2.86mmol) and (1.596mL, (446mg is 1.142mmol) in the suspension in acetonitrile (20mL) 9.14mmol) to be added to the product that is obtained by step 5 to be permitted the uncommon alkali of Buddhist nun.Suspension becomes almost even, becomes the stiff suspension then.After room temperature keeps 30 minutes, mixture is cooled to 0 ℃.The THF solution of adding 2M dimethyl amine (0.571mL, 1.142mmol).After 2 hours, add 1,30 ℃ of maintenance, and 4-thiadiazoles-2-amine (347mg, 3.43mmol).With mixture heating up to 60 ℃ and kept 7 hours, use saturated NH ₄Cl (100mL) cancellation is also used CHCl ₃(4 * 50mL) extractions.With the extract drying (MgSO that merges ₄), concentrate and carry out purifying (use Sunfire S10 30 * 250mm chromatographic column and with 40 to 70% solvent B wash-outs) with reversed-phase HPLC, obtain embodiment 3, it is a crystalline solid, is estimated as two-tfa salt (316.7mg, 38% yield). ¹H NMR (400MHz, and the δ ppm 9.11 of methyl alcohol-d4) (1H, s), 8.28 (1H, dd, J=4.91,1.64Hz), 8.15 (2H, d, J=8.56Hz), 7.70-7.83 (3H, m), 7.54 (2H, d, J=8.31Hz), 7.25 (1H, dd, J=7.43,4.91Hz), 4.69 (1H, s), 3.12 (3H, s), 3.04 (3H, s), 1.19 (6H, s); MS (ES+) m/z:501 (M+H); LC retention time: 3.29 minutes (analytical HPLC method A).

Embodiment 4-9

Embodiment 4-7 prepares in the top described mode of embodiment 3 title compounds that just prepares by the acid that is obtained by embodiment 3 steps 5, remove 5-amino-N-cyclopropyl-1,3, the outer amine that is purchased that also uses of 4-thiadiazoles-2-carboxylic acid amides, described 5-amino-N-cyclopropyl-1,3, the synthetic of 4-thiadiazoles-2-carboxylic acid amides is described in table down.Embodiment 8-9 obtains by embodiment 3-4 is carried out chiral separation, wherein uses SFCChiralcel OJ-H chromatographic column (3 * 25cm, CO ₂/ MeOH 70: 30,120ml/min, 254nm, 40 ℃), both are second peak that elutes from chromatographic column.

5-amino-N-cyclopropyl-1,3,4-thiadiazoles-2-carboxylic acid amides synthetic

To 5-amino-1,3,4-thiadiazoles-2-carboxylic acid, ethyl ester (2g, 11.55mmol) add in the suspension in methyl alcohol (15mL) cyclopropylamine (1.5mL, 21.65mmol).Mixture was stirred 1.5 hours stirring at room 1 hour and at 40 ℃.Add cyclopropylamine (2mL) again.40 ℃ keep 3 hours, 50 ℃ kept 1 hour and 70 ℃ keep 20 minutes after, mixture is concentrated into half volume, water (2.5mL) dilution is heated to and boils, and obtains settled solution and is cooled to room temperature.With solid filtering, with the cold methanol washing, and dry, obtain 5-amino-N-cyclopropyl-1,3,4-thiadiazoles-2-carboxylic acid amides, it is yellow crystals (1.52g, 72% yield).MS (ES+) m/z:185 (M+H); LC retention time: 0.87 minute (analytical HPLC method A).

Embodiment 10

4-(5-(1,1-dimethyl-2-oxo-2-(1,3,4-thiadiazoles-2-base is amino) ethyl)-8-methyl-5H-pyrido [3 ', 2 ': 5,6] pyrans is [2,3-b] pyridine-2-yl also)-N, the N-dimethyl benzamide

Step 1

(30mL, (8g is 45.2mmol) in the solution in THF (100mL) and MeOH (25mL) 60.0mmol) to be added to 2-chloro-6-picoline-3-formic acid with the diethyl ether solution of 2M (trimethyl silyl) diazomethane in room-temperature water bath.After 30 minutes, add HOAc (2mL).Mixture concentrated and and carry out purifying (with 0-20%EtOAc/ hexane wash-out) with silica gel chromatography, obtain 2-chloro-6-picoline-3-methyl-formiate, it is colorless oil (7.77g, 93% yield).MS (ES+) m/z:186 (M+H); LC retention time: 2.64 minutes (analytical HPLC method A).

Step 2

(40.2mL, (14.92mL is 105mmol) in the solution in THF (160mL) 100mmol) dropwise to be added to diisopropylamine at-78 ℃ with the hexane solution of 2.5M BuLi.Mixture was stirred 15 minutes and is cooled to-78 ℃ at 0 ℃.Dropwise add acetonitrile (5.25mL, 100mmol).Solution gradually becomes oyster white.After 1 hour, dropwise add 2-chloro-6-picoline-3-methyl-formiate (7.77g, 41.9mmol) solution in THF (25mL)-78 ℃ of maintenances.Flask also adds with THF (5mL) drip washing.-78 ℃ keep 1 hour after, mixture is with salt solution (100mL) cancellation and to be acidified to pH be about 1.(3 * 100mL) extract the water-based residue with EtOAc.The extract that merges washs with salt solution (50mL), dry (MgSO ₄) and concentrate, obtaining brown oil, it spends the night in placement, and the back is slow solidifies.Solid CH ₂Cl ₂Grind and filter, obtain needed product (3.4115g), it is a pale solid.Filtrate is carried out purifying (with 10-50%EtOAc/ hexane wash-out), the product of getting back (3.9584g) with silica gel chromatography.Total recovery is 90%.MS (ES+) m/z:195 (M+H); LC retention time: 2.09 minutes (analytical HPLC method A).

Step 3

With 4-acetylbenzoic acid (40g; 244mmol), the 40% dimethyl amine aqueous solution (33.0g; 292mmol), N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride (56.1g; 292mmol), I-hydroxybenzotriazole hydrate (44.8g; 292mmol) and N; (85mL is 487mmol) at CH for the N-diisopropylethylamine ₃Mixture among the CN (400mL) concentrates then stirring at room 15 hours.Residue is dissolved in ethyl acetate (1000mL), use H ₂O (2 * 200mL) and salt solution (200mL) washing, dry (MgSO ₄) and concentrate, obtain 4-ethanoyl-N, N-dimethyl benzamide (24g).Crude product need not purifying and promptly is used for next reaction.

Step 4

With thick 4-ethanoyl-N, N-dimethyl benzamide (24.0g) and N, the mixture heating up of dinethylformamide dimethyl acetal (100mL) is cooled to room temperature and concentrated to refluxing and keeping 15 hours.Residue obtains (E)-4-(3-(dimethylamino) acryl)-N with ether washing and vacuum-drying, the N-dimethyl benzamide, and it is brown solid (16g, two step yields are 27%).MS(ES+)m/z：247(M+H)。

Step 5

With Glacial acetic acid (4.81mL; 84mmol) be added to (E)-4-(3-(dimethylamino) acryl)-N; N-dimethyl benzamide (4.137g; 16.80mmol) and 3-(2-chloro-6-picoline-3-yl)-3-oxypropionitrile (3.92g is 20.16mmol) in the brown solution in DMF (30mL).Solution is heated to 120 ℃ and kept 7 hours, is cooled to room temperature and with MeOH (30mL) dilution.Filter the collecting precipitation thing, (3 * 25mL) wash, and vacuum-drying obtains needed product, and it is micro mist red solid (4.629g) with MeOH.Filtrate is concentrated and carry out purifying with silica gel chromatography and (use 3-10%MeOH/CH ₂Cl ₂Wash-out).The cut that will contain product merges also uses 0-10%MeOH/CH again ₂Cl ₂Purifying, the product of getting back, it is brown solid (438mg).The total recovery of product is 5.067g (84% yield).MS (ES+) m/z:360 (M+H); LC retention time: 3.45 minutes (analytical HPLC method A).

Step 6

(3.33g, (7.05g is 19.62mmol) at CH 88mmol) to be added to the product that is obtained by step 5 at 0 ℃ with aliquot with the powder sodium borohydride ₂Cl ₂(218mL) and in the solution among the MeOH (218mL).0 ℃ keep 2 hours after, the saturated NH of mixture ₄Cl (200mL) and water (200mL) cancellation.Separate two-phase.Water layer CH ₂Cl ₂(3 * 100mL) extractions.With the CH that merges ₂Cl ₂Layer concentrates and vacuum-drying, obtains needed product, and it is brown ceramic powder (7.392g).Thick material need not purifying and promptly is used for next reaction.

Step 7

At 0 ℃ of CH that lasts 10 minutes with 1M titanium tetrachloride (IV) ₂Cl ₂(24.54mL 24.54mmol) is added to the alcohol (7.39g) that obtained by step 6 at CH to solution ₂Cl ₂In the suspension (500mL).Gained tawny suspension was stirred 10 minutes at 0 ℃.Dropwise add dimethyl ketene contract methyl alcohol trimethyl silyl alcohol (12.46mL, 61.3mmol).After 1 hour, remove the saturated NaHCO of ice bath and reaction mixture 0 ℃ of maintenance ₃(250mL) cancellation (notes discharging CO ₂).Mixture was stirred 30 minutes and filter through Celite pad., Celite pad CH ₂Cl ₂(250mL) drip washing.Separate the two-phase filtrate layers.Water CH ₂Cl ₂(2 * 100mL) extractions.With the CH that merges ₂Cl ₂Dry mutually (MgSO ₄) and concentrate.Carry out purifying with silica gel chromatography and (use CH ₂Cl ₂Load and with 30% to 100%EtOAc/[CH ₂Cl ₂-hexane (1: 1)] wash-out), obtaining needed product, it is tawny solid (7.78g, two step yields are 89%).MS (ES+) m/z:446 (M+H); LC retention time: 3.54 minutes (analytical HPLC method A).

Step 8

(15.42g, (7.78g is 17.46mmol) in the suspension in DMF (100mL) and tetrahydrofuran (THF) (100mL) 157mmol) to be added to the product that is obtained by step 7 with 2-rosickyite sodium alkoxide.The gained dark mixture is heated to 50 ℃ and kept 5 hours, is cooled to 0 ℃ and come cancellation by careful adding 1N HCl (157mL).Brown solution is concentrated and spend the night 50 ℃ of vacuum-dryings.Residue is absorbed in saturated NH ₄Among the Cl (250mL), to be adjusted to pH be about 2 and use CHCl with 1N NaOH ₃(5 * 150mL) extractions.With the extract drying (MgSO that merges ₄) and concentrate.Carry out purifying with silica gel chromatography and (use CH ₂Cl ₂Load and use 0-10%MeOH/CH ₂Cl ₂Wash-out), obtain needed product, it is brown solid (8.35g).MS (ES+) m/z:432 (M+H); LC retention time: 3.37 minutes (analytical HPLC method A).

Step 9

Two kinds of enantiomers of the acid (3.0g) that is obtained by step 8 use Chiralpak AD-H chromatographic columns to separate.First peak that discovery is obtained by chromatographic column is S enantiomer (1.201g) and is used for the follow-up synthetic of analogue.MS (ES+) m/z:432 (M+H); LC retention time: 3.40 minutes (analytical HPLC method A).

Step 10

Acid (the 26mg that will obtain by step 8,0.039mmol), 1,3, and 4-thiadiazoles-2-amine (22mg, 0.218mmol), N, N-diisopropylethylamine (0.034mL, 0.197mmol) and O-(7-azepine benzo triazol-1-yl)-N, N, N ', (43.8mg is 0.115mmol) at CH for N '-tetramethyl-urea hexafluorophosphate ₃Solution among the CN (1.5mL) stirred 17 hours at 60 ℃.Thick material carries out purifying (Sunfire S10 30 * 250mm chromatographic column, gradient are 55-85% solvent B) with reversed-phase HPLC, obtains embodiment 10, and it is pale solid (17.7mg, 60% yield). ¹H NMR (400MHz, and the δ ppm8.90 of chloroform-d) (1H, s), 8.08 (2H, d, J=8.31Hz), and 7.60-7.69 (1H, m), 7.48-7.60 (4H, m), 7.02 (1H, d, J=7.55Hz), 4.62 (1H, s), 3.19 (3H, s), 3.05 (3H, s), 2.58 (3H, s), 1.26 (3H, s), 1.25 (3H, s); MS (ES+) m/z:515 (M+H); LC retention time: 3.45 minutes (analytical HPLC method A).

Embodiment 11-13

Embodiment 11-13 prepares in the top described mode of embodiment 10 title compounds that just prepares by the S-acid that is obtained by embodiment 10 steps 9, uses the amine that is purchased.

Embodiment 14

4-(5-(1,1-dimethyl-2-oxo-2-(1,3,4-thiadiazoles-2-base is amino) ethyl)-8-methyl-5H-pyrido [3 ', 2 ': 5,6] pyrans is [2,3-b] pyridine-2-yl also)-N-ethyl-N-methyl-benzamide

Step 1

(30mL 60.0mmol) dropwise is added to 2, and (8.00g is 37.5mmol) in the solution in THF (100mL) and MeOH (25mL) for 6-dichloropyridine-3-formic acid with the diethyl ether solution of 2.0M (trimethyl silyl) diazomethane in room-temperature water bath.After 1 hour, add HOAc (4mL).Mixture is stirred until no longer bubbling and concentrated.The gained solid is dissolved in the ethyl acetate of minimum, and with the hexane dilution, and partial vacuum concentrates.White crystalline solid is precipitated out and filters collection.With this process triplicate, obtain the needed product of 4.553g.Mother liquor is concentrated and carry out purifying (with 0-20%EtOAc/ hexane wash-out), the product of getting back (2.48g) with silica gel chromatography.The total amount of product is 7.033g (91% yield).MS (ES+) m/z:206 (M+H); LC retention time: 2.99 minutes (analytical HPLC method A).

Step 2

(32.6mL, (12.11mL is 85mmol) in the solution in THF (100mL) 82mmol) dropwise to be added to diisopropylamine at-78 ℃ with the hexane solution of 2.5M BuLi.Mixture was stirred 15 minutes and is cooled to-78 ℃ at 0 ℃.Dropwise add acetonitrile (4.26mL, 82mmol).Solution gradually becomes oyster white.After 1 hour, dropwise add 2,6-dichloropyridine-3-methyl-formiate (7.00g, 34.0mmol) solution in THF (25mL)-78 ℃ of maintenances.Flask also adds with THF (5mL) drip washing.-78 ℃ keep 1 hour after, mixture is with salt solution (100mL) cancellation, is acidified to pH and is about 1 and with EtOAc (3 * 100mL) extractions.The extract that merges washs with salt solution (50mL), dry (MgSO ₄) and concentrate.Carry out purifying (with 0-5% methyl alcohol/CH with silica gel chromatography ₂Cl ₂Wash-out), obtain needed product, it is yellow solid (4.6374g, 64% yield).MS (ES+) m/z:215 (M+H); LC retention time: 2.45 minutes (analytical HPLC method A).

Step 3

With Glacial acetic acid (2.277mL, 39.8mmol) be added to (E)-4-(dimethylamino) fourth-3-alkene-2-ketone (0.90g, 7.95mmol) and 3-(2,6-dichloropyridine-3-yl)-3-oxypropionitrile (2.052g is 9.54mmol) in the brown solution in DMF (20mL).With mixture heating up to 100 ℃.After 2.5 hours, stop heating 100 ℃ of maintenances.Add MeOH (40mL).Mixture is cooled to 0 ℃ and filtration.(3 * 15mL) washings obtain needed product to the solid that is obtained by filtration, and it is tawny solid (1.239g) with MeOH.Filtrate is concentrated and carry out purifying with silica gel chromatography and (use 0-30%EtOAc/[CH ₂Cl ₂-hexane (1: 4)] wash-out), the product of getting back (0.364g).The total amount of product is 1.603g (82% yield).MS (ES+) m/z:247 (M+H); LC retention time: 3.15 minutes (analytical HPLC method A).

Step 4

The ketone that will be obtained by step 3 (dilute and be cooled to 0 ℃ with methyl alcohol (75mL) by 1.658g, 6.72mmol) dissolving in methylene dichloride (75mL).With aliquot add the particle sodium borohydride (1.272g, 33.6mmol).0 ℃ keep 30 minutes after, the saturated NH of mixture ₄Cl (80mL) and water (80mL) cancellation.The vacuum-evaporation organic solvent.Filter the collecting precipitation thing, (3 * 25mL) washing and vacuum-dryings obtain needed product to water, and it is yellow solid (1.510g, 91% yield).MS (ES+) m/z:249 (M+H); LC retention time: 2.733 minutes (analytical HPLC method A).

Step 5

CH with 1.0M titanium tetrachloride (IV) ₂Cl ₂(6.37mL, (1.320g is 5.31mmol) at CH 6.37mmol) dropwise to be added to the alcohol that is obtained by step 4 at 0 ℃ for solution ₂Cl ₂In the suspension (80mL).0 ℃ keep 10 minutes after, dropwise add dimethyl ketene contract methyl alcohol trimethyl silyl alcohol (2.157mL, 10.62mmol).Suspension gradually becomes dark homogeneous solution.0 ℃ keep 1 hour after, the saturated NaHCO of mixture ₃(80mL) cancellation and filter through Celite pad., Celite pad CH ₂Cl ₂Drip washing.Separate two-phase filtrate.Water CH ₂Cl ₂(2 * 50mL) extractions.With the CH that merges ₂Cl ₂Dry mutually (MgSO ₄) and concentrate.With solid residue at CH ₂Cl ₂Dissolving (50mL) is concentrated into about 10mL and uses 30%EtOAc/ hexane (50mL) dilution.(2 * 20mL) washings obtain needed product, and it is white solid (1.264g) with the solid filtering collection and with the 30%EtOAc/ hexane.Filtrate is concentrated and carry out purifying with silica gel chromatography and (use 10-50%EtOAc/[CH ₂Cl ₂3: 7 mixtures of-hexane] wash-out), the product of getting back (224mg).The total amount of required product is 1.488g (84% yield).MS (ES+) m/z:333 (M+H); LC retention time: 3.40 minutes (analytical HPLC method A).

Step 6

(20mL, (1.50g is 4.51mmol) in the suspension in MeOH (20mL) and THF (20mL) 20.00mmol) to be added to the product that is obtained by step 5 in room temperature with the 1.0N NaOH aqueous solution.After 6 hours, stop heating 80 ℃ of maintenances.The vacuum-evaporation organic solvent.To be adjusted to pH be 1-2 to the water-based residue and solid filtering collected with 1N HCl.Filtrate is used CH ₂Cl ₂(2 * 50mL) extractions.With the extract drying (MgSO that merges ₄) and concentrate, obtain solid, itself and the solid that is obtained by filtration are merged, obtain needed product (1.40g, 97% yield).MS (ES+) m/z:319 (M+H); LC retention time: 3.11 minutes (analytical HPLC method A).

Step 7

Two kinds of enantiomers of the acid (10.7g) that is obtained by step 6 use SFC Chiralpak AD chromatographic columns to separate.First peak that discovery is obtained by the chromatographic column wash-out is S enantiomer (5.54g), and it is Et ₂NH (diethylamide) salt (adds Et ₂NH is to be used for solution the SFC injection).MS (ES+) m/z:319 (M+H); LC retention time: 3.26 minutes (analytical HPLC method A).

Step 8

The acid that obtains by step 6 (30mg, 0.055mmol), 4-(ethyl (methyl) carbamyl) phenyl-boron dihydroxide (22.7mg, 0.110mmol), the 2.0M potassiumphosphate aqueous solution (0.137mL, 0.274mmol) and Pd (PPh ₃) ₄(12.68mg, 0.011mmol) the solution nitrogen purge in DMF (2mL).After 4 hours, mixture is cooled to room temperature 90 ℃ of maintenances, handles, use CH with 1N NaOH (10mL) ₂Cl ₂(2 * 5mL) washings, to be adjusted to pH be 1-2 and use CH with 1N HCl ₂Cl ₂(2 * 30mL) extractions.The extract that merges washs with salt solution (10mL), dry (MgSO ₄) and concentrate.Carry out purifying (Sunfire S10 30 * 250mm chromatographic column, gradient are 20-100% solvent B) with reversed-phase HPLC, obtain needed product, be estimated as two-tfa salt (31mg, 84% yield).MS (ES+) m/z:446 (M+H); LC retention time: 3.35 minutes (analytical HPLC method A).

Step 9

(0.056mL 0.322mmol) dropwise is added to O-(7-azepine benzo triazol-1-yl)-N, N will to be permitted the uncommon alkali of Buddhist nun, N ', N '-tetramethyl-urea hexafluorophosphate (26.2mg, 0.069mmol) and the acid that obtains by step 8 (31mg is 0.046mmol) in the suspension in acetonitrile (2mL).After room temperature keeps 5 minutes, add 1,3,4-thiadiazoles-2-amine (13.96mg, 0.138mmol).60 ℃ keep 7 hours after, mixture is cooled to room temperature, concentrate and carry out purifying (Sunfire S10 30 * 250mm chromatographic column, gradient are 20-100% solvent B) with reversed-phase HPLC, obtain needed product.Impure product further carries out purifying with silica gel chromatography and (uses 0-10%MeOH/CH ₂Cl ₂Wash-out), obtains needed product, be translated into two-tfa salt (18mg, 52% yield). ¹H NMR (400MHz, and the δ ppm 9.11 of methyl alcohol-d4) (1H, s), 8.12 (2H, d, J=8.31Hz), 7.74 (1H, s), 7.68 (1H, d, J=7.55Hz), 7.49 (2H, t, J=7.93Hz), 7.14 (1H, d, J=7.81Hz), 4.64 (1H, s), 3.50-3.71 (1H, m), and 3.30-3.40 (1H, m), 2.97-3.14 (3H, m), 2.52 (3H, s), 1.11-1.35 (9H, m); MS (ES+) m/z:529 (M+H); LC retention time: 3.37 minutes (analytical HPLC method A).

Embodiment 15-19

Embodiment 15-19 prepares in the top described mode of embodiment 14 title compounds that just prepares by the acid that is obtained by embodiment 14 steps 6, uses the boric acid and the 2-amino-1,3 that are purchased, the 4-thiadiazoles.The synthetic of boric acid that is used for embodiment 18 is described in table down.

Synthesizing of 4-(ethyl (methyl) carbamyl)-3-fluorophenyl boric acid

With N-methyl ethyl-amine (1.5mL, 17.46mmol) be added to 4-borono--2-fluorobenzoic acid (1.13g, 6.14mmol) and O-(7-azepine benzo triazol-1-yl)-N, N, N ', (2.54g (carries out ultrasonication to promote dissolving) in DMF 6.68mmol) (10mL) solution to N '-tetramethyl-urea hexafluorophosphate.After room temperature keeps 3 hours, add saturated NH ₄Cl (50mL) and water (10mL).Mixture with dense HCl (～0.5mL) to be acidified to pH be 3.(3 * 50mL) extract mixture with ethyl acetate.The extract that merges washs with salt solution (5mL), dry (MgSO ₄) and concentrate, obtaining the stiff brown oil, its water (7mL) is handled and is placed and spend the night.Remove by filter the white needles thing.Filtrate is carried out purifying (Sunfire S10 30 * 250mm chromatographic column, gradient are 30-50% solvent B) with reversed-phase HPLC, obtains needed product, and it is white glass shape solid (1.1036g, 80% yield).LC retention time: 2.49 minutes (analytical HPLC method A).

Embodiment 20

2-(2-(dimethylamino)-8-methyl-5H-pyrido [3 ', 2 ': 5,6] pyrans is [2,3-b] pyridine-5-yl also)-2-methyl-N-(1,3,4-thiadiazoles-2-yl) propionic acid amide

Step 1

(30mg, 0.094mmol) (0.5mL is 3.99mmol) at CH with the 40% dimethyl amine aqueous solution by acid that embodiment 14 steps 6 obtain ₃Mixture among CN (0.5mL) and the MeOH (0.5mL) 150 ℃ with microwave treatment 1 hour, be cooled to room temperature and concentrate.Residue carries out purifying (SunfireS10 30 * 250mm chromatographic column, gradient are 20-100% solvent B) with reversed-phase HPLC, obtains needed product, and it is tfa salt (20mg, 48% yield).MS (ES+) m/z:328 (M+H); LC retention time: 3.16 minutes (analytical HPLC method A).

Step 2

Acid (the 20mg that will obtain by step 1,0.045mmol), 1,3,4-thiadiazoles-2-amine (9.16mg, 0.091mmol), N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride (17.37mg, 0.091mmol), the I-hydroxybenzotriazole hydrate (13.88mg, 0.091mmol) and N, (0.040mL is 0.227mmol) at CH for the N-diisopropylethylamine ₃Mixture heating up to 80 among the CN (2mL) ℃.80 ℃ keep 6 hours after, mixture concentrated and carry out purifying (Sunfire S1030 * 250mm chromatographic column, gradient is 20-100% solvent B) with reversed-phase HPLC, obtain needed product, be estimated as three-tfa salt (5mg, 15% yield). ¹H NMR (400MHz, and the δ ppm 9.09 of methyl alcohol-d4) (1H, s), 7.62 (1H, d, J=7.55Hz), 7.38 (1H, d, J=8.56Hz), 7.08 (1H, d, J=7.81Hz), 6.42 (1H, d, J=8.56Hz), 4.43 (1H, s), 3.07 (6H, s), 2.50 (3H, s), and 1.07-1.20 (6H, m); MS (ES+) m/z:411 (M+H); LC retention time: 3.30 minutes (analytical HPLC method A).

Embodiment 21-35

Embodiment 21-35 prepares in the top described mode of embodiment 14 title compounds that just prepares by the S-enantiomer that is obtained by embodiment 14 steps 7, uses the boric acid and the amine that are purchased.

Embodiment 36

(4-((5S)-5-(1,1-dimethyl-2-oxo-2-(1,3,4-thiadiazoles-2-base is amino) ethyl)-8-methyl-5H-pyrido [3 ', 2 ': 5,6] (methyl) sulfoxide { (4-((5S)-5-(1 phenyl pyrans [2,3-b] pyridine-2-yl also)), 1-dimethyl-2-oxo-2-(1,3,4-thiadiazol-2-ylamino) ethyl)-8-methyl-5H-pyrido[3 ', 2 ': 5,6] pyrano[2,3-b] pyridin-2-yl) phenyl) (methyl) sulfoniumolate}

(37.7mg, 0.061mmol) solution in water (1mL) dropwise is added to embodiment 29 at 0 ℃ (30mg is 0.061mmol) in the solution in MeOH (1mL) with potassium hydrogen persulfate.After 1 hour, the saturated Na of mixture ₂SO ₃(1mL) cancellation with EtOAc (60mL) dilution, is used saturated NaHCO ₃(2 * 5mL) and salt solution (5mL) washing, dry (MgSO ₄) and concentrate, obtaining embodiment 36, it is white solid (29mg, 94% yield). ¹H NMR (400MHz, the δ ppm 9.02 of methyl alcohol-d4) (1H, s), 8.24 (2H, d, J=8.56Hz), 7.69-7.87 (4H, m), 7.58 (1H, d, J=7.55Hz), 7.05 (1H, d, J=7.55Hz), 4.63 (1H, s), 2.81 (3H, s), 2.46 (3H, s), 1.12 (6H, s); MS (ES+) m/z:506 (M+H); LC retention time: 3.09 minutes (analytical HPLC method A).

Embodiment 37

2-methyl-2-((5S)-2-methyl-8-(4-(methyl sulphonyl) phenyl)-5H-pyrido [3 ', 2 ': 5,6] pyrans is [2,3-b] pyridine-5-yl also)-N-(1,3,4-thiadiazoles-2-yl) propionic acid amide

(43.8mg, 0.071mmol) solution in water (1mL) dropwise is added to embodiment 36 in room temperature (18mg is 0.036mmol) in the solution in MeOH (1mL) with potassium hydrogen persulfate.After 3 hours, the saturated Na of mixture ₂SO ₃(1mL) cancellation with EtOAc (60mL) dilution, is used saturated NaHCO ₃(2 * 5mL) and salt solution (5mL) washing, dry (MgSO ₄) and concentrate, obtaining embodiment 37, it is white solid (17mg, 92% yield). ¹H NMR (400MHz, and the δ ppm 9.10 of methyl alcohol-d4) (1H, s), 8.26 (2H, d, J=8.56Hz), 8.01 (2H, d, J=8.56Hz), 7.69-7.83 (2H, m, J=5.79Hz), 7.59 (1H, d, J=7.81Hz), 7.08 (1H, d, J=7.55Hz), 4.62 (1H, s), 3.17 (3H, s), 2.49 (3H, s), 1.16 (6H, d, J=3.02Hz); MS (ES+) m/z:522 (M+H); LC retention time: 3.12 minutes (analytical HPLC method A).

Embodiment 38-42

Embodiment 38-42 prepares in the top described mode of embodiment 14 title compounds that just prepares by the S-enantiomer that is obtained by embodiment 14 steps 7.The synthetic of required boric acid is described in table down.

Synthesizing of 4-(azetidine-1-carbonyl) phenyl-boron dihydroxide:

With 4-borono-phenylformic acid (527.4mg, 3.18mmol), O-(7-azepine benzo triazol-1-yl)-N, N, N ', (1.61g, 4.23mmol) and N, (1.665mL is 9.53mmol) at CH for the N-diisopropylethylamine for N '-tetramethyl-urea hexafluorophosphate ₃Solution among the CN (40mL) was stirring at room 30 minutes.The adding azetidine (0.321mL, 4.76mmol).Stir after 3 days, mixture is concentrated and carry out purifying (Sunfire S10 30 * 250mm chromatographic column, gradient are 10-40% solvent B) with reversed-phase HPLC, obtain needed product, it is white solid (361mg, 55% yield). ¹H NMR (500MHz, the δ ppm 7.68 of methyl alcohol-d4) (2H, d, J=7.70Hz), 7.60 (2H, d, J=7.97Hz), 4.37 (2H, t, J=7.56Hz), 4.19 (2H, t, J=7.84Hz), 2.36 (2H, quintets); MS (ES+) m/z:206 (M+H); LC retention time: 2.01 minutes (analytical HPLC method A).

Synthesizing of 4-(3,3-two fluoropyrrolidines-1-carbonyl)-3-fluorophenyl boric acid

With 4-borono--2-fluorobenzoic acid (1.00g, 5.44mmol), N, N-diisopropylethylamine (2.85mL, 16.31mmol), O-(7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethyl-urea hexafluorophosphate (2.163g, 5.69mmol) and 3, (1.00g, 6.97mmol) solution in DMF (6mL) was stirring at room 22 hours for 3-difluoro pyrrolidine hydrochloride.After adding 1N HCl (16mL), mixture extracts with ethyl acetate (40mL).HPLC analyzes and shows that water still contains product.Water solid NaOH and K ₂CO ₃Be neutralized to pH and be 7 and use ethyl acetate extraction.With the extract drying (MgSO that merges ₄) and concentrate, obtain the stiff brown oil.The isopyknic water treatment of this residue.The white crystalline solid that will form from mixture is filtered and is collected and wash with a small amount of ether, obtains needed product (0.7811g).Filtrate is carried out purifying (Sunfire S10 30 * 250mm chromatographic column, gradient are 30-50% solvent B), the product of getting back (0.5632g) with reversed-phase HPLC.The total recovery of product is 1.344g (91% yield).MS (ES+) m/z:274 (M+H); LC retention time: 2.68 minutes (analytical HPLC method A).

Synthesizing of 4-(3,3-two fluoropyrrolidines-1-carbonyl) phenyl-boron dihydroxide

4-borono-phenylformic acid (500mg, 3.01mmol), N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride (866mg, 4.52mmol) and I-hydroxybenzotriazole (554mg, 3.62mmol) mixture in acetonitrile (25mL) becomes solution with ultrasonication until it.Add N, and the N-diisopropylethylamine (1.579mL, 9.04mmol) with 3,3-two fluoropyrrolidines (484mg, 4.52mmol).After room temperature keeps 30 minutes, the saturated NH of mixture ₄Cl (50mL) cancellation is also used EtOAc (3 *) extraction.The extract that merges salt solution and water washing, dry (Na ₂SO ₄) and concentrate.Carry out purifying with reversed-phase HPLC, obtain needed product (0.250mg, 33% yield).MS (ES+) m/z:256 (M+H); LC retention time: 1.87 minutes (analytical HPLC method A).

4-(cyclopropyl (methyl) carbamyl) phenyl-boron dihydroxide

With N, the N-diisopropylethylamine (1.693mL, 9.69mmol) be added to 4-borono-phenylformic acid (321.7mg, 1.939mmol) and O-(7-azepine benzo triazol-1-yl)-N, N, N ', (806.4mg is 2.121mmol) at CH for N '-tetramethyl-urea hexafluorophosphate ₃In the suspension among the CN (20mL).After room temperature keeps 50 minutes, and adding N-methyl cyclopentamine oxalate (315.8mg, 1.960mmol).In room temperature and after keeping 1.25 hours, mixture carries out purifying (Sunfire S10 30 * 250mm chromatographic column, gradient are 30-50% solvent B) with reversed-phase HPLC, obtains needed product (303.6mg, 72% yield).MS (ES+) m/z:220 (M+H); LC retention time: 2.40 minutes (analytical HPLC method A).

3-fluoro-4-(morpholine-4-carbonyl) phenyl-boron dihydroxide

With 4-borono--2-fluorobenzoic acid (1.000g, 5.44mmol), morpholine (0.951mL, 10.87mmol) and O-(7-azepine benzo triazol-1-yl)-N, N, N ', (2.103g, 5.53mmol) solution in DMF (10mL) was also used 1NHCl (20mL) cancellation in 16 hours in stirring at room to N '-tetramethyl-urea hexafluorophosphate.Trial extracts with EtOAc, but product can not be extracted fully from aqueous phase.Merge two-phase, concentrate and carry out purifying (Sunfire S10 30 * 250mm chromatographic column, gradient are 30-45% solvent B) with reversed-phase HPLC, obtain needed product, it is white solid (1.2385g, 90% yield).MS (ES+) m/z:254 (M+H); LC retention time: 2.06 minutes (analytical HPLC method A).

Embodiment 43-48

Embodiment 43-48 prepares in the top described mode of embodiment 14 title compounds that just prepares by the S-enantiomer that is obtained by embodiment 14 steps 7.The synthetic of most of required amino thiadiazoles is described in table down.The amino thiadiazoles that is used for embodiment 43 and 44 is described under the table of embodiment 4-7.

5-amino-N-methyl isophthalic acid, 3,4-thiadiazoles-2-carboxylic acid amides synthetic:

To 5-amino-1,3,4-thiadiazoles-2-carboxylic acid, ethyl ester (106mg, 0.612mmol) add in the suspension in methyl alcohol (1.5mL) 33wt% (weight percent) methylamine ethanolic soln (0.5mL, 4.00mmol).Mixture stirring at room 6 hours, is heated to 70 ℃ and cooling.Mixture is concentrated, mix with water and freeze-drying, obtain 5-amino-N-methyl isophthalic acid, 3,4-thiadiazoles-2-carboxylic acid amides, it is white solid (99mg). ¹H NMR (400MHz, DMSO-d6) δ ppm 8.69 (q, J=4.8Hz, 1H), 7.70 (s, 2H), 2.73 (d, J=4.78Hz, 3H); MS (ES+) m/z:159 (M+H); LC retention time: 0.44 minute (analytical HPLC method A).

5-amino-N, N-dimethyl-1,3,4-thiadiazoles-2-carboxylic acid amides tfa salt synthetic:

To 5-amino-1,3,4-thiadiazoles-2-carboxylic acid, ethyl ester (200mg, 1.155mmol) add in the suspension in EtOH (3mL) dimethyl amine (1mL, 7.90mmol).Mixture was stirred 2 hours and concentrated at 90 ℃.Residue carries out purifying with reversed-phase HPLC (to be used Sunfire S10 30 * 250mm chromatographic column and uses 0-40% solvent B (90%MeOH-10%H ₂O-0.1%TFA)/solvent orange 2 A (10%MeOH-90%H ₂O-0.1%TFA) wash-out), obtain needed product, it is tfa salt (50mg, 15% yield).MS (ES+) m/z:173 (M+H); LC retention time: 0.66 minute (analytical HPLC method A).

5-amino-N-ethyl-1,3,4-thiadiazoles-2-carboxylic acid amides synthetic:

To 5-amino-1,3,4-thiadiazoles-2-carboxylic acid, ethyl ester (200mg, 1.155mmol) add in the suspension in methyl alcohol (1.5mL) the 70% ethylamine aqueous solution (0.5mL, 6.29mmol).Mixture in stirred overnight at room temperature, is concentrated, mix with water and freeze-drying, obtain 5-amino-N-ethyl-1,3,4-thiadiazoles-2-carboxylic acid amides, it is faint yellow solid (200mg).MS (ES+) m/z:173 (M+H); LC retention time: 0.70 minute (analytical HPLC method A).

Embodiment 49

N-cyclobutyl-5-((2-((5S)-2-(4-(ethyl (methyl) carbamyl) phenyl)-8-methyl-5H-pyrido [3 ', 2 ': 5,6] pyrans is [2,3-b] pyridine-5-yl also)-2-methylpropionyl) amino)-1,3,4-thiadiazoles-2-carboxylic acid amides

(199mg, (20mg is 0.028mmol) in the solution in MeOH (1mL) 2.80mmol) to be added to embodiment 32 with cyclobutyl amine.Mixture stirring at room 15 hours, was stirred 5 hours and concentrated at 60 ℃.Residue carries out purifying with reversed-phase HPLC (to be used Sunfire S10 30 * 250mm chromatographic column and uses 40-100% solvent B (90%MeOH-10%H ₂O-0.1%TFA)/solvent orange 2 A (10%MeOH-90%H ₂O-0.1%TFA) wash-out).The cut that will contain product concentrates and dilutes with ethyl acetate (60mL), uses saturated NaHCO ₃(2 * 5mL) and salt solution (5mL) washing, dry (MgSO ₄) and concentrate, obtaining embodiment 49, it is white solid (11mg, 63% yield). ¹H NMR (500MHz, and the δ ppm 8.14 of methyl alcohol-d4) (2H, d, J=8.25Hz), 7.74 (2H, s), 7.60 (1H, d, J=7.70Hz), and 7.41-7.55 (2H, m), 7.09 (1H, d, J=7.70Hz), 4.63 (1H, s), 4.38-4.59 (1H, m), 3.50-3.73 (1H, m), 3.59 (1H, d, J=7.15Hz), 3.31-3.46 (1H, m), and 2.95-3.15 (3H, m), 2.49 (3H, s), and 2.26-2.42 (2H, m), 2.09-2.27 (2H, m), and 1.71-1.89 (2H, m), 1.20-1.45 (3H, m), and 1.14-1.25 (6H, m); MS (ES+) m/z:626 (M+H); LC retention time: 3.24 minutes (analytical HPLC method A).

Embodiment 50

4-((5S)-5-(1,1-dimethyl-2-((5-(morpholine-4-base carbonyl)-1,3,4-thiadiazoles-2-yl) amino)-the 2-oxoethyl)-8-methyl-5H-pyrido [3 ', 2 ': 5,6] pyrans [2,3-b] pyridine-2-yl also)-N-ethyl-N-methyl-benzamide

(244mg, (20mg is 0.028mmol) in the solution in MeOH (1mL) 2.80mmol) to be added to embodiment 32 with morpholine.60 ℃ keep 3 hours after, add again morpholine (244mg, 2.80mmol).Mixture was stirred 24 hours at 70 ℃, be cooled to room temperature and concentrated.Residue carries out purifying with reversed-phase HPLC and (uses Sunfire S10 30 * 250mm chromatographic column also with 40 to 100% solvent B (90%MeOH-10%H ₂O-0.1%TFA)/solvent orange 2 A (10%MeOH-90%H ₂O-0.1%TFA) wash-out).The cut that will contain product concentrates and dilutes with ethyl acetate (60mL), uses saturated NaHCO ₃(2 * 5mL) and salt solution (5mL) washing, dry (MgSO ₄) and concentrate, obtaining embodiment 50, it is white solid (9mg, 50% yield). ¹H NMR (500MHz, the δ ppm 8.15 of methyl alcohol-d4) (2H, d, J=8.80Hz), 7.75 (2H, s), 7.61 (1H, d, J=7.70Hz), 7.43-7.56 (2H, m), 7.10 (1H, d, J=7.70Hz), 4.64 (1H, s), 4.20-4.40 (2H, m), and 3.68-3.91 (6H, m), 3.51-3.66 (1H, m), 3.31-3.44 (1H, m), 2.96-3.15 (3H, m), 2.50 (3H, s), and 1.21-1.40 (3H, m), 1.15-1.19 (6H, m); MS (ES+) m/z:642 (M+H); LC retention time: 3.31 minutes (analytical HPLC method A).

Embodiment 51

2-((2-((5S)-2-(4-(dimethylamino formyl radical) phenyl)-8-methyl-5H-pyrido [3 ', 2 ': 5,6] pyrans is [2,3-b] pyridine-5-yl also)-2-methylpropionyl) amino)-N-methyl isophthalic acid, 3-thiazole-5-carboxylic acid amides

Step 1

To thiazolamine-5-carboxylic acid, ethyl ester (3.1g, 18mmol) and Boc ₂O (one contract tert-Butyl dicarbonate) (5.0mL, 22mmol) add in the solution in anhydrous THF (40mL) DMAP (0.15g, 1.3mmol).Reaction mixture was stirred 19 hours under room temperature and nitrogen atmosphere.Slowly add heptane (20mL) and with mixture stirring at room 1 hour.With the solid filtering separated and with the mixture of ethyl acetate and heptane (1: 1; 2 * 5mL) washings obtain needed product (2.9g), and it is a yellow solid.Mother liquor is concentrated and solid residue is boiled with ethyl acetate (6mL), cooling is filtered and is washed with cold ethyl acetate (1mL), obtains second batch of required compound (1.3g), and it is a yellow solid.The total recovery of 2-(tert-butoxycarbonyl amino) thiazole-5-carboxylic acid ethyl ester is 4.2g (85% yield).MS measured value: (M+H) ⁺=273.

Step 2

To the 2-of vigorous stirring (tert-butoxycarbonyl amino) thiazole-5-carboxylic acid ethyl ester (4.2g, 15mmol) add in the suspension in methyl alcohol (11mL) the 2M NaOH aqueous solution (22mL, 44.0mmol).With suspension in stirred overnight at room temperature.With the mixture vacuum concentration to remove methyl alcohol.Residual aqueous suspension with 6N HCl acidified aqueous solution to pH be about 1-2.Mixture was stirred 1 hour and handled with ultrasonic wave frequently.With solid filtering, wash with water and drying, obtain 2-(tert-butoxycarbonyl amino) thiazole-5-carboxylic acid (3.7g, 100% yield), it is a white solid.MS measured value: (M+H-Boc) ⁺=145.

Step 3

Under room temperature and nitrogen atmosphere to 2-(tert-butoxycarbonyl amino) thiazole-5-carboxylic acid (1.0g, 4.1mmol), I-hydroxybenzotriazole hydrate (0.63g, 4.1mmol), N, N-diisopropylethylamine (4.3mL, 24mmol) and methylamine hydrochloride (0.83g, (2.4g is 12mmol) and in stirred overnight at room temperature 12mmol) to add WSCDI in the heterogeneous mixture in anhydrous acetonitrile (20mL).With the reaction mixture vacuum concentration.In residue, add saturated sodium bicarbonate aqueous solution (20mL), ethyl acetate (6mL) and heptane (2mL).With the solid filtering of separating, water (2 * 2mL) and ether (2 * 4mL) washings and dry obtain 5-(methyl carbamyl) thiazol-2-yl t-butyl carbamate (0.77g, 73% yield), and it is a white solid.MS measured value: (M+H) ⁺=258; ¹H NMR (400MHz, the δ ppm7.83 of methyl alcohol-d4) (s, 1H), 2.87 (s, 3H), 1.55 (s, 9H).

Step 4

(0.77g 3.0mmol) is added in water-bath among the refrigerative TFA (1.5mL) with 5-(methyl carbamyl) thiazol-2-yl t-butyl carbamate.With gained solution stirring at room 1.5 hours.Add second crowd of TFA (1.5mL) and reaction mixture was stirred 30 minutes at 40 ℃, then vacuum concentration.In residue, add the 1M HCl aqueous solution (3.0mL, 3.0mmol) and deionized water (2.0mL) and solution decompression is concentrated.Freeze-drying, (hydrochloride, 750mg), it is a white powder to obtain 2-amino-N-methylthiazol-5-carboxylic acid amides.MS measured value: (M+H) ⁺=158.Crude product need not to be further purified and promptly in statu quo is used for next step.

Step 5

S-acid (the 20mg that under nitrogen atmosphere, will obtain by embodiment 10 steps 9,0.046mmol), 2-amino-N-methylthiazol-5-carboxylic acid amides (hydrochloride, 35mg, 0.14mmol), O-(7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethyl-urea hexafluorophosphate (35mg, 0.093mmol), N, N-diisopropylethylamine (0.040mL, 0.23mmol) and the mixture of anhydrous acetonitrile (0.5mL) stirring at room 10 minutes, stirred 4 hours and stirred 1.5 hours at 60 ℃ at 80 ℃.Mixture is filtered and dissolving in methyl alcohol (0.5mL).(YMC S5 20 * 100mm moves 10 minutes, and solvent orange 2 A is 10%MeOH: 90%H to carry out purifying with reversed-phase HPLC ₂O: 0.1%TFA, solvent B are 90%MeOH: 10%H ₂O: 0.1%TFA), obtain embodiment 51, it is tfa salt (11mg, 30% yield). ¹H NMR (400MHz, and the δ ppm 8.16 of methyl alcohol-d4) (d, J=8.31Hz, 2H), 7.97 (s, 1H), 7.77 (s, 2H), 7.66 (d, J=7.55Hz, 1H), 7.54 (d, J=8.31Hz, 2H), 7.13 (d, J=7.55Hz, 1H), 4.65 (s, 1H), 3.13 (s, 3H), 3.05 (s, 3H), 2.90 (s, 3H), 2.52 (s, 3H), 1.17 (s, 6H); MS measured value: (M+H) ⁺=571.

Embodiment 52

4-((5S)-5-(1,1-dimethyl-2-((5-(morpholine-4-base carbonyl)-1,3-thiazoles-2-yl) amino)-2-oxoethyl)-8-methyl-5H-pyrido [3 ', 2 ': 5,6] pyrans is [2,3-b] pyridine-2-yl also)-N, the N-dimethyl benzamide

Embodiment 52 prepares according to just synthetic embodiment 51 described methods. ¹H NMR (400MHz, and the δ ppm 8.16 of methyl alcohol-d4) (d, J=8.31Hz, 2H), 7.80 (s, 1H), 7.77 (s, 2H), 7.64 (d, J=7.55Hz, 1H), 7.55 (d, J=8.31Hz, 2H), 7.12 (d, J=7.55Hz, 1H), 4.65 (s, 1H), 3.72-3.82 (m, 8H), 3.13 (s, 3H), 3.05 (s, 3H), 2.51 (s, 3H), 1.17 (s, 6H); MS measured value: (M+H) ⁺=627.

Embodiment 53

N-cyclopropyl-2-((2-((5S)-2-(4-(dimethylamino formyl radical) phenyl)-8-methyl-5H-pyrido [3 ', 2 ': 5,6] pyrans is [2,3-b] pyridine-5-yl also)-2-methylpropionyl) amino)-1,3-thiazoles-5-carboxylic acid amides

Embodiment 53 prepares according to just synthetic embodiment 51 described methods. ¹H NMR (500MHz, the δ ppm 8.16 of methyl alcohol-d4) (d, J=8.25Hz, 2H), 7.98 (s, 1H), 7.76 (s, 2H), 7.63 (d, J=7.70Hz, 1H), 7.54 (d, J=8.25Hz, 2H), 7.11 (d, J=7.70Hz, 1H), 4.65 (s, 1H), 3.13 (s, 3H), 3.05 (s, 3H), 2.79-2.85 (m, 1H), 2.51 (s, 3H), 1.16 (s, 6H), and 0.78-0.83 (m, 2H), 0.62-0.66 (m, 2H); MS measured value: (M+H) ⁺=597.

Embodiment 54

4-(8-chloro-5-(1,1-dimethyl-2-oxo-2-(1,3,4-thiadiazoles-2-base is amino) ethyl)-5H-pyrido [3 ', 2 ': 5,6] pyrans is [2,3-b] pyridine-2-yl also)-N, the N-dimethyl benzamide

Step 1

With (E)-4-(3-(dimethylamino) acryl)-N; N-dimethyl benzamide (1.1g; 4.47mmol), 3-(2; 6-dichloropyridine-3-yl)-3-oxypropionitrile (1.344g; 6.25mmol) and acetate (1.278mL; 22.33mmol) solution in N,N-dimethylacetamide (10mL) stirred 6.5 hours under 120 ℃ and nitrogen and be cooled to room temperature.After adding entry (120mL), filter the collecting precipitation thing and carry out purifying (with 50-100%EtOAc/ hexane wash-out), obtain yellow solid with silica gel chromatography.Impure material is stirred with MeOH (10mL).Solid residue is filtered collection, obtain needed product, it is pale solid (0.551g, 33% yield).MS (ES+) m/z:380 (M+H); LC retention time: 3.68 minutes (analytical HPLC method A).

Step 2

(226.3mg, (503.4mg is 1.325mmol) at CH 5.98mmol) to be added to the ketone that is obtained by step 1 at 0 ℃ with sodium borohydride ₂Cl ₂(22mL) and in the solution among the MeOH (33mL).After 1 hour, the saturated NH of mixture ₄Cl (10mL) and water (10mL) cancellation.The vacuum-evaporation organic solvent.Add EtOAc (50mL).Mixture dissolves until all throw outs with ultrasonication.(3 * 50mL) extract with EtOAc to separate two-phase and water.The EtOAc extract that merges washs with salt solution (5mL), dry (MgSO ₄) and concentrate, obtaining needed product, it is pale solid (0.45g, 89% yield).Thick material need not to be further purified and promptly is used for next reaction.

Step 3

CH with 1.0M titanium tetrachloride (IV) ₂Cl ₂(2.95mL, (450mg is 1.179mmol) at CH 2.95mmol) to be added to the alcohol that is obtained by step 2 at 0 ℃ for solution ₂Cl ₂In the suspension (100mL).0 ℃ keep 30 minutes after, 0 ℃ add dimethyl ketene contract methyl alcohol trimethyl silyl alcohol (1.197mL, 5.89mmol).Mixture was stirred 1 hour, use saturated NaHCO at 0 ℃ ₃(75mL) cancellation, and in stirred overnight at room temperature.Separate two-phase.Water CH ₂Cl ₂(25mL) extraction.The organic extract that merges is concentrated and carry out purifying (with 50-100%EtOAc/ hexane wash-out) with silica gel chromatography, obtain needed product, it is faint yellow solid (0.5079g, 92% yield).MS (ES+) m/z:466 (M+H); LC retention time: 3.68 minutes (analytical HPLC method A).

Step 4

The ester that under microwave, will obtain by step 3 (207.6mg, 0.446mmol) and lithium chloride (953mg, 22.48mmol) suspension in DMF (5mL) was 220 ℃ of heating 30 minutes.Pour mixture into saturated NH ₄Among the Cl (50mL), with 1N HCl (～0.5mL) be acidified to pH be 4-5 and with EtOAc (1 * 50mL, 2 * 20mL) extraction.The extract that merges washs with salt solution (5mL), dry (MgSO ₄) and concentrate.Residue water (10mL) is handled.The throw out that forms is filtered collection, with the EtOAc washing, obtain needed product, it is pale powder (0.1291g, 64% yield).MS (ES+) m/z:452 (M+H); LC retention time: 3.55 minutes (analytical HPLC method A).

Step 5

Acid (the 15.3mg that will obtain by step 4,0.034mmol), 1,3, and 4-thiadiazoles-2-amine (6.9mg, 0.068mmol), O-(7-azepine benzo triazol-1-yl)-N, N, N ', and N '-tetramethyl-urea hexafluorophosphate (22.5mg, 0.059mmol) and N, (5.91 μ L are 0.034mmol) at CH for the N-diisopropylethylamine ₃Solution among the CN (1mL) stirred 18 hours at 60 ℃.Thick material carries out purifying (Sunfire S10 30 * 250mm chromatographic column, gradient are 55 to 75% solvent B) with reversed-phase HPLC, obtains embodiment 54, and it is a white solid, is estimated as two-tfa salt (13mg, 44% yield). ¹H NMR (400MHz, the δ ppm 8.90 of chloroform-d) (1H, s), 8.09 (2H, d, J=8.31Hz), 7.57-7.65 (2H, m), 7.53 (3H, m), 7.16 (1H, d, J=7.81Hz), 4.62 (1H, s), 3.19 (3H, s), 3.06 (3H, s), 1.25 (6H, s); MS (ES+) m/z:535 (M+H); LC retention time: 3.56 minutes (analytical HPLC method A).

Embodiment 55

Step 1

(87mg, 0.187mmol) (167.7mg, 1.709mmol) solution in DMF (3.5mL) heated 1 hour at 50 ℃ the ester that will be obtained by embodiment 54 steps 3 with 2-rosickyite sodium alkoxide.After being cooled to room temperature, mixture extracts with 1N HCl (35mL) acidifying and with ethyl acetate (20mL).Organic extract salt water washing, dry (MgSO ₄) and carry out purifying (with 40-90%EtOAc/ hexane wash-out) with silica gel chromatography, obtaining needed product, it is pale yellow powder (54.2mg, 55% yield).MS (ES+) m/z:492 (M+H); LC retention time: 4.11 minutes (analytical HPLC method A).

Step 2

Embodiment 55 uses the acid that is obtained by step 2 to prepare according to the condition similar to embodiment 54 steps 5. ¹H NMR (400MHz, and the δ ppm 8.88 of chloroform-d) (1H, s), 8.07-8.13 (2H, m), 7.50-7.64 (4H, m), 7.32 (1H, d, J=7.81Hz), 6.95 (1H, d, J=8.06Hz), 4.52 (1H, s), and 4.06-4.19 (1H, m), 3.19 (3H, s), 3.05 (3H, s), 1.42 (6H, t, J=6.67Hz), 1.25 (6H, s); MS (ES+) m/z:575 (M+H); LC retention time: 4.10 minutes (analytical HPLC method A).

Embodiment 56-57

Embodiment 56-57 uses the condition of embodiment 54 steps 5 and replaces 1,3 with suitable amine, and 4-thiadiazoles-2-amine prepares.

Embodiment 58

4-(8-chloro-5-(1,1-dimethyl-2-((5-methyl isophthalic acid, 3,4-thiadiazoles-2-yl) amino)-2-oxoethyl)-5H-pyrido [3 ', 2 ': 5,6] pyrans is [2,3-b] pyridine-2-yl also)-N-ethyl-N-methyl-benzamide

Step 1

(8.00g, (9.7g is 23.18mmol) at CHCl 46.4mmol) to be added to the ester that is obtained by embodiment 3 steps 4 with metachloroperbenzoic acid ₃In the suspension (200mL).After room temperature keeps 15 hours, add another part metachloroperbenzoic acid (8.0g).After 56 hours, the saturated Na of mixture ₂SO ₃Solution (150mL) cancellation was also stirred 1 hour.Separate organic layer, use saturated Na ₂CO ₃(4 * 100mL), saturated NaHCO ₃(100mL) and salt solution (100mL) washing, dry (MgSO ₄) and concentrate, obtaining needed product, it is that purity is 93% material (9.20g, 85% yield). ¹H NMR (400MHz, δ ppm 8.30 (1H, dd, the J=6.42 of chloroform-d), 1.38Hz), 8.16-8.26 (2H, m), 8.08-8.17 (2H, m), and 7.67-7.80 (2H, m), 6.98-7.19 (2H, m), 4.52 (1H, s), 3.94 (3H, s), 3.66-3.77 (3H, m), and 0.87-1.17 (6H, m); MS (ES+) m/z:435 (M+H); LC retention time: 3.28 minutes (analytical HPLC method A).

Step 2

(8.56g is 19.70mmol) at POCl for the pyridine oxide that will be obtained by step 1 ₃Suspension (100mL) is heated to 110 ℃ and kept 2 hours, is cooled to room temperature, pours in the frozen water and filters.Solid CH ₂Cl ₂(1.2L) with saturated Na ₂CO ₃(400mL) handle.With the gained suspension stirring at room 1 hour.Separate organic suspension and use H ₂O (2 * 200mL) washings and filtration.With solid vacuum-drying, obtain brown solid (4.5g).Filtrate is concentrated, obtain another batch brown solid (4.0g).Two batches of solids that contain pure products are not merged, among DMSO (400mL), dissolve, use CH ₂Cl ₂(1200mL) dilution, and use H ₂O (3 * 300mL) and salt solution (300mL) washing, dry (MgSO ₄) and to be concentrated into volume be about 100mL.Throw out is filtered and uses CH ₂Cl ₂Washing obtains needed product, and it is brown solid (1.8g ,～85% purity).It is about 100mL that the water that merges is concentrated into volume.Throw out is filtered and vacuum-drying, obtain second batch of product (3.0g ,～60% purity).

Step 3

(10mL 10.00mmol) is added in the suspension of product (1.00g ,～85% purity) in MeOH (20mL) that is obtained by step 2 in room temperature with the 1.0N NaOH aqueous solution.80 ℃ keep 6 hours after, the vacuum-evaporation organic solvent.It is 1-2 that the water-based residue is adjusted to pH with 1N HCl.Carry out purifying (Sunfire S10 30 * 250mm chromatographic column, gradient are 20 to 100% solvent B) with the solid filtering collection and with reversed-phase HPLC, obtain needed product, be estimated as two-tfa salt (250mg, 21% yield). ¹HNMR (400MHz, DMSO-d6) δ ppm 8.24 (2H, d, J=8.31Hz), 8.06 (2H, d, J=8.56Hz), 8.01 (1H, d), and 7.91-7.98 (1H, m), 7.88 (1H, d, J=7.81Hz), 7.44 (1H, d, J=7.81Hz), 4.52 (1H, s), 0.93 (6H, s), MS (ES+) m/z:425 (M+H); LC retention time: 3.38 minutes (analytical HPLC method A).

Step 4

Use and step 3 similar methods, will be converted into diprotic acid by second batch of ester (2.0g, 60% purity) that step 2 obtains.Two kinds of enantiomers use Chiralpak AD chromatographic column to separate.First peak that collection elutes from chromatographic column obtains needed enantiomer (0.354g, 41% yield). ¹H NMR (400MHz, the δ ppm 8.09-8.21 of methyl alcohol-d4) (m, 4H), 7.94 (d, J=8.06Hz, 1H), 7.86 (dd, J=7.93,1.89Hz, 2H), 7.31 (d, J=7.81Hz, 1H), 4.55 (s, 1H), 1.04 (s, 3H), 1.02 (s, 3H); MS (ES+) m/z:425 (M+H); LC retention time: 3.71 minutes (analytical HPLC method A).

Step 5

(0.107mL 0.613mmol) is added to O-(7-azepine benzo triazol-1-yl)-N, N will to be permitted the uncommon alkali of Buddhist nun, N ', N '-tetramethyl-urea hexafluorophosphate (69.9mg, 0.184mmol) and the acid that obtains by step 3 (40mg is 0.061mmol) in the suspension in acetonitrile (2mL).Gained solution stirring at room 30 minutes, is cooled to 0 ℃ then.The THF solution of adding 0.5M N-ethyl dimethylamine (0.123mL, 0.061mmol).After 1.5 hours, add the 5-methyl isophthalic acid 0 ℃ of maintenance, 3,4-thiadiazoles-2-amine (21.17mg, 0.184mmol).Mixture was stirred 15 hours at 55 ℃, concentrate and carry out purifying (Sunfire S10 30 * 250mm chromatographic column, gradient are 20 to 100% solvent B), obtain embodiment 58, be estimated as two-tfa salt (20mg, 41% yield) with reversed-phase HPLC. ¹H NMR (400MHz, and the δ ppm8.11 of methyl alcohol-d4) (2H, d, J=8.56Hz), 7.75 (2H, s), 7.70 (1H, d, J=7.81Hz), 7.49 (2H, t, J=8.18Hz), 7.26 (1H, d, J=7.81Hz), 4.64 (1H, s), 3.32-3.67 (2H, m), 2.95-3.20 (3H, m), 2.70 (3H, s), 1.03-1.43 (9H, m); MS (ES+) m/z:563 (M+H); LC retention time: 3.52 minutes (analytical HPLC method A).

Embodiment 59-63

Embodiment 59-61 uses the condition of embodiment 58 steps 5 to prepare, and uses the amine that is purchased or prepare before.Embodiment 62-63 uses the condition of embodiment 58 steps 5 to prepare, and uses homochiral acid that is obtained by embodiment 58 steps 4 and the amine that is purchased or prepare before.

Embodiment 64

4-(5-(1,1-dimethyl-2-oxo-2-(1,3,4-thiadiazoles-2-base is amino) ethyl)-8-vinyl-5H-pyrido [3 ', 2 ': 5,6] pyrans is [2,3-b] pyridine-2-yl also)-N, the N-dimethyl benzamide

Step 1

The acid that will obtain by embodiment 54 steps 4 (22mg, 0.049mmol), Pd (Ph ₃P) ₄(0.024mL, 0.049mmol) solution in DMF (1.5mL) is found time and is backwashed twice with nitrogen for (6.8mg, 5.88 μ mol) and the 2M potassiumphosphate aqueous solution.After 11 hours, pour mixture into saturated NH 90 ℃ of maintenances ₄(3 * 10mL) extract among the Cl (10mL) and with EtOAc.The extract that merges washs with salt solution (2mL), dry (Na ₂SO ₄) and concentrate, obtain brown oil.Thick material need not to be further purified and promptly is used for next reaction.

Step 2

The thick acid, 1,3 that will obtain by step 1, and 4-thiadiazoles-2-amine (7.7mg, 0.076mmol), O-(7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethyl-urea hexafluorophosphate (19mg, 0.050mmol) and N, (30 μ L are 0.172mmol) at CH for the N-diisopropylethylamine ₃Solution among the CN (1mL) stirred 15 hours at 60 ℃, be cooled to room temperature and carry out purifying (Sunfire S10 30 * 250mm chromatographic column, gradient are 60 to 85% solvent B), obtain embodiment 64 with reversed-phase HPLC, it is white powder (12.4mg, two step yields are 34%). ¹H NMR (400MHz, and the δ ppm 8.89 of chloroform-d) (1H, s), 8.11 (2H, d, J=8.31Hz), and 7.53-7.64 (5H, m), 7.14 (1H, d, J=7.81Hz), 6.77 (1H, dd, J=17.37,10.58Hz), 6.34 (1H, dd, J=17.37,1.01Hz), 5.56 (1H, d, J=11.58Hz), 4.58 (1H, s), 3.19 (3H, s), 3.05 (3H, s), 1.25 (6H, s); MS (ES+) m/z:527 (M+H); LC retention time: 3.59 minutes (analytical HPLC method A).

Embodiment 65

4-(5-(1,1-dimethyl-2-oxo-2-(1,3,4-thiadiazoles-2-base is amino) ethyl)-8-phenyl-5H-pyrido [3 ', 2 ': 5,6] pyrans is [2,3-b] pyridine-2-yl also)-N, the N-dimethyl benzamide

Embodiment 65 uses the two step consecutive reactions of synthetic embodiment 64 to be synthesized by acid and the phenyl-boron dihydroxide that embodiment 54 steps 4 obtain. ¹H NMR (400MHz, the δ ppm 8.90 of chloroform-d) (1H, s), 8.13 (2H, d, J=8.31Hz), 8.08 (2H, d, J=6.80Hz), 7.43-7.67 (9H, m), 4.64 (1H, s), 3.18 (3H, s), 3.05 (3H, s), 1.29 (3H, wide unimodal), 1.28 (3H, wide unimodal); MS (ES+) m/z:577 (M+H); LC retention time: 3.96 minutes (analytical HPLC method A).

Embodiment 66

4-(8-cyano group-5-(1,1-dimethyl-2-oxo-2-(1,3,4-thiadiazoles-2-base is amino) ethyl)-5H-pyrido [3 ', 2 ': 5,6] pyrans is [2,3-b] pyridine-2-yl also)-N, the N-dimethyl benzamide

Step 1

The acid that will obtain by embodiment 54 steps 4 (24.8mg, 0.055mmol), zinc cyanide (16.7mg, 0.142mmol) and Pd (Ph ₃P) ₄(14.5mg, 0.013mmol) suspension in DMF (1mL) is found time and is backwashed twice with nitrogen.After 2.5 hours, mixture carries out purifying (Sunfire S10 30 * 250mm chromatographic column, gradient are 50 to 80% solvent B) with reversed-phase HPLC, obtains needed product 100 ℃ of maintenances, and it is white powder (16.6mg, 45% yield).MS (ES+) m/z:443 (M+H); LC retention time: 3.13 minutes (analytical HPLC method A).

Step 2

Embodiment 66 is just using the acid that is obtained by step 1 to synthesize under the described condition of embodiment 64 steps 2. ¹H NMR (400MHz, and the δ ppm 8.92 of chloroform-d) (1H, s), 8.10 (2H, d, J=8.31Hz), 7.77 (1H, d, J=7.81Hz), 7.64 (2H, q, J=7.89Hz), 7.51-7.57 (3H, m), 4.75 (1H, s), 3.19 (3H, s), 3.05 (3H, s), (1.27 3H, wide unimodal), 1.26 (3H, wide unimodal); MS (ES+) m/z:526 (M+H); LC retention time: 3.34 minutes (analytical HPLC method A).

Embodiment 67

4-(8-(dimethylamino)-5-(1,1-dimethyl-2-oxo-2-(1,3,4-thiadiazoles-2-base is amino) ethyl)-5H-pyrido [3 ', 2 ': 5,6] pyrans is [2,3-b] pyridine-2-yl also)-N, the N-dimethyl benzamide

Step 1

Ester (the 39mg that trial will be obtained by embodiment 54 steps 3,0.084mmol) and the 40% dimethyl amine aqueous solution (1mL, 7.90mmol) solution in MeOH (0.5mL) is heated to 220 ℃ under microwave, but owing to high pressure (＞19psi (pound/square inch)) stops.Then mixture is heated under microwave～150 ℃ and kept 1 hour.Carry out purifying (Sunfire S10 30 * 250mm chromatographic column, gradient are 55 to 85% solvent B) with reversed-phase HPLC, obtain needed product (47.3mg, 70% yield).MS (ES+) m/z:461 (M+H); LC retention time: 3.67 minutes (analytical HPLC method A).

Step 2

Embodiment 67 is just using the acid that is obtained by step 1 to synthesize under the described condition of embodiment 64 steps 2. ¹H NMR (400MHz, and the δ ppm 8.88 of chloroform-d) (1H, s), 8.10 (2H, d, J=8.31Hz), 7.47-7.62 (4H, m), 7.28 (1H, d, J=8.56Hz), 6.29 (1H, d, J=8.31Hz), 4.41 (1H, s), 3.19 (3H, s), 3.11 (6H, s), 3.05 (3H, s), 1.24 (6H, s); MS (ES+) m/z:544 (M+H); LC retention time: 3.69 minutes (analytical HPLC method A).

Embodiment 68

4-(8-(dimethylamino)-5-(1,1-dimethyl-2-((5-methyl isophthalic acid, 3,4-thiadiazoles-2-yl) amino)-2-oxoethyl)-5H-pyrido [3 ', 2 ': 5,6] pyrans is [2,3-b] pyridine-2-yl also)-N, the N-dimethyl benzamide

Embodiment 68 is just using the acid that is obtained by embodiment 67 steps 1 to synthesize under the described condition of embodiment 64 steps 2. ¹H NMR (400MHz, and the δ ppm 8.11 of chloroform-d) (2H, d, J=8.56Hz), 7.45-7.61 (4H, m), 7.24-7.28 (1H, m), 6.27 (1H, d, J=8.31Hz), 4.40 (1H, s), 3.17 (3H, s), 3.10 (6H, s), 3.04 (3H, s), 2.76 (3H, s), 1.22 (6H, s); MS (ES+) m/z:558 (M+H); LC retention time: 3.84 minutes (analytical HPLC method A).

Embodiment 69

4-(5-(1,1-dimethyl-2-oxo-2-(1,3,4-thiadiazoles-2-base is amino) ethyl)-8-(morpholine-4-yl)-5H-pyrido [3 ', 2 ': 5,6] pyrans is [2,3-b] pyridine-2-yl also)-N, the N-dimethyl benzamide

Under just synthetic embodiment 67 described conditions, make ester and the morpholine reaction that obtains by embodiment 54 steps 3 and be converted into embodiment 69. ¹H NMR (400MHz, and the δ ppm 8.88 of chloroform-d) (1H, s), 8.10 (2H, d, J=8.31Hz), and 7.56-7.61 (1H, m), 7.48-7.56 (3H, m), 7.32 (1H, d, J=8.31Hz), 6.38 (1H, d, J=8.31Hz), 4.44 (1H, s), 3.82 (4H, t, J=4.78Hz), 3.47-3.63 (4H, m), 3.19 (3H, s), 3.05 (3H, s), 1.25 (6H, s); MS (ES+) m/z:586 (M+H); LC retention time: 3.62 minutes (analytical HPLC method A).

Embodiment 70

4-(5-(1,1-dimethyl-2-oxo-2-(1,3,4-thiadiazoles-2-base is amino) ethyl)-8-(tetramethyleneimine-1-yl)-5H-pyrido [3 ', 2 ': 5,6] pyrans is [2,3-b] pyridine-2-yl also)-N, the N-dimethyl benzamide

Under just synthetic embodiment 67 described conditions, make acid and the tetramethyleneimine reaction that obtains by embodiment 54 steps 4 and be converted into embodiment 70. ¹H NMR (400MHz, the δ ppm 8.90 of chloroform-d) (1H, s), 8.06 (2H, d, J=8.31Hz), 7.56 (2H, s), 7.51 (2H, d, J=8.31Hz), 7.42 (1H, d, J=8.81Hz), 6.27 (1H, d, J=8.56Hz), 4.43 (1H, s), 3.53-3.64 (4H, m), 3.19 (3H, s), 3.06 (3H, s), 2.00-2.16 (4H, m), 1.25 (3H, s), 1.23 (3H, s); MS (ES+) m/z:570 (M+H); LC retention time: 3.88 minutes (analytical HPLC method A).

Embodiment 71-72

Embodiment 71-72 uses the acid that is obtained by embodiment 58 steps 4 to synthesize according to the condition of embodiment 67 steps 1 and embodiment 58 steps 5.

Embodiment 73

4-(8-(dimethylamino)-5-(1,1-dimethyl-2-oxo-2-(1,3,4-thiadiazoles-2-base is amino) ethyl)-5H-pyrido [3 ', 2 ': 5,6] pyrans is [2,3-b] pyridine-2-yl also)-2-fluoro-N, the N-dimethyl benzamide

Step 1

(12.33mL, (4.39mL is 30.8mmol) in the solution in THF (100mL) 30.8mmol) dropwise to be added to diisopropylamine at-78 ℃ with the hexane solution of 2.5M BuLi.Mixture was stirred 15 minutes and is cooled to-78 ℃ at 0 ℃.Dropwise add 2-chloropyridine (3.5g, THF 30.8mmol) (15mL) solution.Solution gradually becomes glassy yellow.After 1 hour, dropwise add 2-chloropyridine-3-formaldehyde (4.80g, 33.9mmol) suspension in THF (80mL)-78 ℃ of maintenances.Flask THF (5mL) also adds with drip washing.-78 ℃ keep 2 hours after, the saturated NH of mixture ₄Cl (200mL) cancellation, being acidified to pH with dense HCl is 4, and (150mL, 2 * 50mL) extract with ether.The extract that merges washs with salt solution (10mL), dry (MgSO ₄) and concentrate.Carry out purifying (with 10-100%EtOAc/ hexane wash-out) with silica gel chromatography, obtain needed product, it is light brown powder (2.48g, 26% yield).MS (ES+) m/z:255 (M+H); LC retention time: 2.38 minutes (analytical HPLC method A).

Step 2

(5.18g, (1.88g is 7.37mmol) in the solution in methylene dichloride (100mL) and THF (20mL) 12.21mmol) to be added to two (2-chloropyridine-3-yl) methyl alcohol with the high idodine of Dai Si-Martin.After room temperature keeps 1.5 hours, add 1.4M NaHSO ₃(50mL) and with mixture stirring at room 20 minutes.After the solids removed by filtration, separate two-phase filtrate.The saturated NaHCO of water ₃(200mL) alkalize to pH and be 8 and use CH ₂Cl ₂(100mL) extraction.With the CH that merges ₂Cl ₂Dry mutually (MgSO ₄) and concentrate.Carry out purifying (with 0-100%EtOAc/ hexane wash-out) with silica gel chromatography, obtain needed product, it is light brown powder (1.87g, 91% yield).MS (ES+) m/z:253 (M+H); LC retention time: 2.79 minutes (analytical HPLC method A).

Step 3

(1.87g, 7.39mmol) suspension in MeOH (18mL) is added to sodium methylate (1.36g is 25.2mmol) in the suspension in MeOH (7mL) with two (2-chloropyridine-3-yl) ketone.Mixture is heated under nitrogen refluxes and kept 7 hours.Add NaOMe (sodium methylate) again (2.91g).After refluxing again 14 hours, vacuum evaporating solvent.The gained material dissolved in water (50mL) and with EtOAc (2 * 50mL) extractions.The extract pH that merges is 7 damping fluid (10mL) and salt solution (10mL) washing, dry (MgSO ₄) and concentrate, obtaining needed product, it is white solid (1.7669g, 98% yield).MS(ES+)m/z：245(M+H)。

Step 4

With two (2-methoxypyridine-3-yl) ketone (1.7549g, 7.18mmol) and pyridine hydrochloride (7.3g, solid mixture 63.2mmol) assign in two microwave bottles and each comfortable 220 ℃ with microwave treatment 10 minutes.Combined mixture and by ultrasonic wave and at CHCl ₃(200mL) and in the water (100mL) dissolve.After separating two-phase, water CHCl ₃(2 * 100mL) extractions.The CHCl that merges ₃Through MgSO ₄Dry and concentrated, obtain needed product, it is tawny crystalline solid (1.07g, 75% yield).MS (ES+) m/z:199 (M+H); LC retention time: 2.35 minutes (analytical HPLC method A).

Step 5

(1.021g, (1.07g is 5.40mmol) at CH 27.0mmol) to be added to the ketone that is obtained by step 4 with sodium borohydride ₂Cl ₂(5mL) and in the suspension among the MeOH (25mL).At 1 hour time point with 2 hours time points add sodium borohydride (0.5g and 0.3g) again and mixture stirred spend the night.Add methylene dichloride (100mL), saturated NH ₄Cl (50mL) and water (50mL).Separate two-phase.Water CH ₂Cl ₂(3 * 100mL) and EtOAc (1 * 100mL) extraction.Merge all organic phases, with salt solution (10mL) washing, dry (MgSO ₄) and concentrate, obtaining needed product, it is faint yellow solid (1.11g, 89% yield).MS (ES+) m/z:201 (M+H); LC retention time: 1.93 minutes (analytical HPLC method A).

Step 6

CH with 1.0M titanium tetrachloride (IV) ₂Cl ₂(12.06mL, (1.11g is 4.82mmol) at CH 12.06mmol) to be added to the alcohol that is obtained by step 5 at 0 ℃ for solution ₂Cl ₂In the suspension (200mL).0 ℃ keep 1 hour after, add dimethyl ketene contract methyl alcohol trimethyl silyl alcohol (4.90mL, 24.12mmol).0 ℃ keep 1 hour after, the saturated NaHCO of mixture ₃(75mL) cancellation is in stirring at room 30 minutes and filtration.Separate two-phase filtrate.Water CH ₂Cl ₂(1 * 100mL) extraction.The CH that merges ₂Cl ₂Use salt solution (5mL) washing mutually, dry (MgSO ₄) and concentrate.Carry out purifying (with 0-100%EtOAc/ hexane wash-out) with silica gel chromatography, obtain needed product, it is white solid (1.08g, 79% yield).MS (ES+) m/z:285 (M+H); LC retention time: 2.91 minutes (analytical HPLC method A).

Step 7

(22.31mL, 218mmol) (0.392g, (1.035g is 3.64mmol) at CH 1.573mmol) to be added to the ester that is obtained by step 6 with methyl trioxy-rhenium (VII) [methyltrioxorhenium (VII)] with 30% aqueous hydrogen peroxide solution ₂Cl ₂In the solution (40mL).After 1 hour, add methyl trioxy-rhenium (VII) again (0.5461g).After 2 hours, add methyl trioxy-rhenium (VII) again (0.5372g) and hydrogen peroxide (22mL).After 3 hours, add methyl trioxy-rhenium (VII) again (1.89g) and hydrogen peroxide (22mL).After 24 hours, slowly add MnO altogether ₂Aqueous suspension (0.5g) is to induce H ₂O ₂Decomposition.Two-phase mixture was stirred 1 hour and separation.Find that water contains the major part in the required product, uses CH ₂Cl ₂(3 * 50mL) washings also concentrate.Carry out purifying (with 10% methyl alcohol/CH with silica gel chromatography ₂Cl ₂Wash-out), obtain impure product, it is pale solid (3.68g).Part above-mentioned substance (2.08g) carries out purifying (Sunfire S10 30 * 250mm chromatographic column, gradient are 0-21% solvent B) with reversed-phase HPLC, obtains needed product, and it is white solid (355mg).MS (ES+) m/z:317 (M+H); LC retention time: 1.60 minutes (analytical HPLC method A).

Step 8

The product that will obtain by step 7 (313.6mg, 0.991mmol) and POCl ₃(4mL, mixture heating up to 100 42.9mmol) ℃ and keeping 20 hours be cooled to room temperature and pour into～the 100mL mixture of ice and water in.Mixture is under agitation used solid NaHCO ₃Being neutralized to pH is 5 also usefulness EtOAc (2 * 50mL) extractions.The extract that merges is concentrated and carry out purifying with silica gel chromatography and (use 0-30%EtOAc/CH ₂Cl ₂Wash-out), obtain needed product, it is white solid (0.1358g, 34% yield).MS (ES+) m/z:353 (M+H); LC retention time: 3.55 minutes (analytical HPLC method A).

Step 9

The product that obtains by step 8 (127.6mg, 0.361mmol) and lithium chloride (220mg, 5.19mmol) suspension in DMF (3mL) at 220 ℃ with microwave treatment 30 minutes.Mixture carries out purifying (YMC 30 * 250mm ODS-A chromatographic column, gradient are 45-90% solvent B) with reversed-phase HPLC, obtains product A (26mg) and product B (19mg).The sign of A: MS (ES+) m/z:339 (M+H); LC retention time: 3.38 minutes (analytical HPLC method A).The sign of B: MS (ES+) m/z:348 (M+H); LC retention time: 3.58 minutes (analytical HPLC method A).

Step 10-11

Embodiment 73 is according to preparing to embodiment 14 steps 8 condition similar with 9. ¹HNMR (400MHz, and the δ ppm 9.07 of methyl alcohol-d3) (1H, s), 7.86-7.97 (2H, m), 7.69 (2H, s), 7.45 (1H, t, J=7.43Hz), 7.37 (1H, d, J=8.56Hz), 6.40 (1H, d, J=8.56Hz), 4.47 (1H, s), 3.11 (3H, s), 3.06 (6H, s), 2.96 (3H, s), 1.14 (3H, s), 1.13 (3H, s); MS (ES+) m/z:562 (M+H); LC retention time: 3.76 minutes (analytical HPLC method A).

Embodiment 74-80

Embodiment 74-80 prepares in the top described mode of embodiment 14 title compounds that just prepares by the S-enantiomer that is obtained by embodiment 14 steps 7, uses the boric acid and the amine that are purchased.

Embodiment 81

2-((5S)-2-(4-(ethyl sulfinyl) phenyl)-8-methyl-5H-pyrido [3 ', 2 ': 5,6] pyrans is [2,3-b] pyridine-5-yl also)-2-methyl-N-(1,3,4-thiadiazoles-2-yl) propionic acid amide

(17.2mg, 0.028mmol) solution in water (0.5mL) dropwise is added to embodiment 78 2-tfa salt at 0 ℃ (30mg is 0.061mmol) in the solution in MeOH (0.5mL) with potassium hydrogen persulfate.1.5 after hour, mixture 1M Na ₂SO ₃Solution (1mL) cancellation, and stir and spend the night.Mixture is concentrated, be absorbed in CH ₂Cl ₂In and be loaded into preparation property silica-gel plate (150A, thickness be 1000 μ m, on 20 * 20cm), and use 5%MeOH/CH ₂Cl ₂Launch.Collect main band, obtain embodiment 81, it is white solid (7.0mg, 47% yield). ¹H NMR (500MHz, the δ ppm 8.92 of chloroform-d) (1H, s), 8.23 (2H, dd, J=8.52,1.65Hz), 7.76 (1H, d, J=7.70Hz), 7.70 (2H, d, J=8.25Hz), 7.58 (1H, dd, J=7.97,2.20Hz), 7.54 (1H, d, J=7.70Hz), 6.95 (1H, d, J=7.42Hz), 4.84 (1H, s), 2.91-3.03 (1H, m), 2.75-2.87 (1H, m), 2.54 (3H, s), 1.30 (3H, s), 1.27 (3H, s), 1.22 (3H, t, J=7.42Hz); MS (ES+) m/z:520 (M+H); LC retention time: 3.46 minutes (analytical HPLC method A).

Embodiment 82

2-((5S)-2-(4-(sec.-propyl sulfinyl) phenyl)-8-methyl-5H-pyrido [3 ', 2 ': 5,6] pyrans is [2,3-b] pyridine-5-yl also)-2-methyl-N-(1,3,4-thiadiazoles-2-yl) propionic acid amide

According to embodiment 14 steps 8 just and 9 and embodiment 81 described conditions, will be converted into embodiment 82 by the S-enantiomer that embodiment 14 steps 7 obtain. ¹H NMR (500MHz, the δ ppm 8.92 of chloroform-d) (1H, s), 8.22 (2H, dd, J=8.52,1.65Hz), 7.76 (1H, d, J=7.42Hz), 7.68 (2H, d, J=8.52Hz), 7.59 (1H, dd, J=7.70,2.20Hz), 7.54 (1H, d, J=7.42Hz), 6.95 (1H, d, J=7.70Hz), 4.83 (1H, s), 2.83-2.96 (1H, m), 2.54 (3H, s), 1.29 (3H, d, J=6.87Hz), 1.27 (3H, s), 1.26 (3H, s), 1.16 (3H, d, J=6.87Hz); MS (ES+) m/z:534 (M+H); LC retention time: 3.59 minutes (analytical HPLC method A).

Embodiment 83

2-((5S)-2-(4-(sec.-propyl alkylsulfonyl) phenyl)-8-methyl-5H-pyrido [3 ', 2 ': 5,6] pyrans is [2,3-b] pyridine-5-yl also)-2-methyl-N-(1,3,4-thiadiazoles-2-yl) propionic acid amide

According to regard to embodiment 81 described conditions, embodiment 82 is converted into embodiment 83. ¹HNMR (500MHz, the δ ppm 8.91 of chloroform-d) (1H, s), 8.26 (2H, d, J=8.52Hz), 7.97 (2H, d, J=8.52Hz), 7.75 (1H, d, J=7.97Hz), 7.60 (1H, d, J=7.70Hz), 7.52 (1H, d, J=7.70Hz), 6.96 (1H, d, J=7.70Hz), 4.77 (1H, s), 3.18-3.29 (1H, m), 2.54 (3H, s), 1.32 (6H, d, J=6.87Hz), 1.28 (3H, s), 1.26 (3H, s); MS (ES+) m/z:550 (M+H); LC retention time: 3.59 minutes (analytical HPLC method A).

Embodiment 84

4-(5-(1,1-dimethyl-2-oxo-2-(1,3,4-thiadiazoles-2-base is amino) ethyl)-9-oxidation-5H-pyrido [3 ', 2 ': 5,6] pyrans is [2,3-b] pyridine-2-yl also)-N-ethyl-N-methyl-benzamide

(0.5mL, 4.89mmol) (11mg, (36.6mg is 0.071mmol) in the solution in methylene dichloride (1mL) 0.044mmol) to be added to embodiment 9 with methyl trioxy-rhenium (VII) with 30% aqueous hydrogen peroxide solution.After room temperature kept 4 hours, mixture concentrated and with preparation property reversed-phase HPLC carry out purifying (last 30 minutes 45-75% solvent B, 40mL/min, Sunfire 30 * 250mm), obtain embodiment 84, it is tfa salt (11.8mg, 25% yield). ¹H NMR (500MHz, and the δ ppm 9.09 of methyl alcohol-d4) (2H, s), 8.42-8.47 (2H, m), 8.10-8.17 (4H, m), 7.82-7.89 (4H, m), 7.61 (2H, d, J=7.15Hz), 7.51 (4H, t, J=8.39Hz), 7.32 (2H, dd, J=7.70,6.60Hz), 4.87 (2H, s), 3.61 (2H, q, J=7.06Hz), 3.35 (2H, q, J=7.06Hz), 3.10 (3H, s), 3.01 (3H, s), 1.27 (3H, t, J=7.15Hz), 1.25 (6H, s), 1.23 (6H, s), 1.17 (3H, t, J=7.15Hz), 1: 1 mixture of two kinds of acid amides rotational isomers; MS (ES+) m/z:531 (M+H); LC retention time: 3.04 minutes (analytical HPLC method A).

Embodiment 85-87

Embodiment 85-87 uses suitable amine to prepare by embodiment 32 according to the condition similar to synthetic embodiment 50.

Embodiment 88

5-((2-methyl-2-((5S)-2-methyl-8-(4-(morpholine-4-base carbonyl) phenyl)-5H-pyrans is [2,3-b:6,5-b '] two pyridines-5-yl also) propionyl) amino)-N-(tetrahydrochysene-2H-pyrans-4-yl)-1,3,4-thiadiazoles-2-carboxylic acid amides

Step 1-2

According to the operation of embodiment 14 steps 8 and 9, make the acid that obtains by embodiment 14 steps 7 and suitable boric acid and amino thiadiazoles coupling, obtain needed product. ¹H NMR (400MHz, and the δ ppm 8.09-8.17 of chloroform-d) (2H, m), 7.79 (1H, t, J=7.69Hz), 7.45-7.63 (4H, m), 6.91-7.02 (1H, m), 4.73 (1H, s), 4.56 (2H, q, J=7.03Hz), 3.38-3.91 (8H, m), 2.54 (3H, s), 1.48 (3H, t, J=7.14Hz), 1.19-1.33 (6H, m); MS (ES+) m/z:629 (M+H); LC retention time: 3.75 minutes (analytical HPLC method B).

Step 3

(40mg 0.064mmol) adds entry (0.6mL) and LiOH-H in the solution in THF (2mL) to the compound that is obtained by step 2 ₂O (6.7mg, 0.16mmol).With mixture at stirred overnight at room temperature and vacuum concentration.Be absorbed in residue in the Virahol and be concentrated into drying, obtain lithium salts.To lithium salts (20mg, 0.033mmol) and tetrahydrochysene-2H-pyrans-4-amine (16.7mg, 0.17mmol) add in the mixture in DMF (3mL) BOP (29.2mg 0.066mmol) and DIEA (42.6mg, 0.33mmol).Stirring at room 2 hours and be absorbed in the ethyl acetate (50mL), it uses saturated NH with mixture ₄Cl (20mL) and NaHCO ₃(20mL) washing is through Na ₂SO ₄Dry also vacuum concentration.Crude product carries out purifying with preparation property HPLC, obtains needed product, and it is tfa salt (13mg, 49.2% yield). ¹HNMR (400MHz, methyl alcohol-d ₄) δ ppm 8.07 (2H, d, J=8.35Hz), 7.67 (2H, s), 7.54 (1H, d, J=7.69Hz), 7.45 (2H, d, J=8.35Hz), 7.02 (1H, d, J=7.69Hz), 4.55 (1H, s), 3.97-4.12 (1H, m), 3.83-3.96 (2H, m), 3.68 (6H, wide unimodal), 3.35-3.51 (4H, m), 2.41 (3H, s), 1.82 (2H, dd, J=12.63,2.31Hz), 1.56-1.74 (2H, m), 1.09 (6H, s); MS (ES+) m/z:684 (M+H); LC retention time: 3.59 minutes (analytical HPLC method B).

Embodiment 89

2-((5S)-2-(4-(1-hydroxyl-1-methylethyl) phenyl)-8-methyl-5H-pyrido [3 ', 2 ': 5,6] pyrans is [2,3-b] pyridine-5-yl also)-2-methyl-N-(1,3,4-thiadiazoles-2-yl) propionic acid amide

Step 1

According to the operation of embodiment 14 steps 8, make the acid and the coupling of 4-acetylbenzene ylboronic acid that obtain by embodiment 14 steps 7, obtain needed product.MS (ES+) m/z:403 (M+H); LC retention time: 2.85 minutes (analytical HPLC method B).

Step 2

Under-78 ℃ and nitrogen to the ketone that obtains by step 1 (60mg, 0.15mmol) add in the solution in anhydrous THF (2mL) methyl-magnesium-bromide solution (concentration is the diethyl ether solution of 3M, 0.50mL, 1.5mmol).After room temperature kept 30 minutes, add 10% aqueous solution of citric acid with pH regulator to 6.(3 * 1mL) extract mixture with ethyl acetate.With the extract drying (Na that merges ₂SO ₄), concentrate and carry out purifying with reversed-phase HPLC, obtain needed product (31mg, 50% yield).MS (ES+) m/z:419 (M+H); LC retention time: 2.92 minutes (analytical HPLC method B).

Step 3

According to regard to the described condition of embodiment 14 steps 9, make the acid and the amino thiadiazoles coupling that obtain by step 2, obtain embodiment 89. ¹H NMR (400MHz, the δ ppm 1.13-1.20 of chloroform-d) (m, 6H) 1.55 (s, 6H) 2.49 (s, 3H) 4.52 (s, 1H) 6.91 (d, J=7.78Hz, 1H) 7.39-7.55 (m, 5H) 7.94 (d, J=8.28Hz, 2H) 8.83 (s, 1H); MS (ES+) m/z:502 (M+H); LC retention time: 2.96 minutes (analytical HPLC method B).

Embodiment 90

1-(4-((5S)-5-(1,1-dimethyl-2-oxo-2-(1,3,4-thiadiazoles-2-base is amino) ethyl)-8-methyl-5H-pyrido [3 ', 2 ': 5,6] pyrans is [2,3-b] pyridine-2-yl also) benzoyl)-D-dried meat acid amides

{1-(4-((5S)-5-(1，1-dimethyl-2-oxo-2-(1，3，4-thiadiazol-2-ylamino)ethyl)-8-methyl-5H-pyrido[3’，2’：5，6]pyrano[2，3-b]pyridin-2-yl)benzoyl)-D-prolinamide}

According to the condition of embodiment 14 steps 8 and 9, make the acid that obtains by embodiment 14 steps 7 with (R)-4-(2-carbamyl tetramethyleneimine-1-carbonyl) phenyl-boron dihydroxide and 2-amino-1,3, the coupling of 4-thiadiazoles obtains embodiment 90. ¹H NMR (400MHz, δ ppm 0.79-0.84 (m, 4H) 0.99 (d, the J=10.54Hz of chloroform-d), 6H) 2.29 (s, 2H) 2.33 (s, 3H) 4.15 (s, 1H) 4.36 (s, 1H) 6.77 (dd, J=12.92,7.65Hz, 1H) 6.86-6.92 (m, 1H) 7.25 (d, J=7.78Hz, 1H) 7.31-7.42 (m, 4H) 7.86 (d, J=8.28Hz, and 2H) 8.67 (s, 1H); MS (ES+) m/z:584 (M+H); LC retention time: 2.52 minutes (analytical HPLC method B).

Embodiment 91

1-(4-((5S)-5-(1,1-dimethyl-2-((5-methyl isophthalic acid, 3,4-thiadiazoles-2-yl) amino)-2-oxoethyl)-8-methyl-5H-pyrido [3 ', 2 ': 5,6] pyrans is [2,3-b] pyridine-2-yl also) benzoyl)-D-dried meat acid amides

{1-(4-((5S)-5-(1，1-dimethyl-2-((5-methyl-1，3，4-thiadiazol-2-yl)amino)-2-oxoethyl)-8-methyl-5H-pyrido[3’，2’：5，6]pyrano[2，3-b]pyridin-2-yl)benzoyl)-D-prolinamide}

According to the condition of embodiment 14 steps 8 and 9, make the acid that obtains by embodiment 14 steps 7 with (R)-4-(2-carbamyl tetramethyleneimine-1-carbonyl) phenyl-boron dihydroxide and 2-amino-5-methyl isophthalic acid, 3, the coupling of 4-thiadiazoles obtains embodiment 91. ¹H NMR (400MHz, δ ppm 1.13 (d, J=14.31Hz, 6H) 1.84 (d of chloroform-d), J=6.78Hz, 1H) 1.98-2.07 (m, 1H) 2.07-2.18 (m, 1H) 2.25-2.37 (m, 1H) 2.49 (s, 3H) 2.69 (s, 3H) 3.42-3.62 (m, 2H) 4.54 (s, 1H) 4.75 (dd, J=7.78,5.52Hz, 1H) 6.93 (d, J=7.53Hz, 1H) 7.40-7.59 (m, 5H) 8.00 (d, J=8.28Hz, 2H); MS (ES+) m/z:598 (M+H); LC retention time: 2.73 minutes (analytical HPLC method B).

Embodiment 92

2-methyl-2-((5S)-2-methyl-8-(4-(morpholine-4-base carbonyl) phenyl)-5H-pyrido [3 ', 2 ': 5,6] pyrans is [2,3-b] pyridine-5-yl also)-N-(2-methyl-2H-tetrazolium-5-yl) propionic acid amide

Step 1

According to the operation of embodiment 14 steps 8, make the acid and morpholino (4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenyl) the ketone coupling that obtain by embodiment 14 steps 7, obtain needed product.MS (ES+) m/z:474 (M+H); LC retention time: 2.62 minutes (analytical HPLC method B).

Step 2

To the acid that obtains by step 1 (30mg, 0.063mmol) add respectively in the solution in THF (5mL) methylsulfonyl chloride (9.87 μ L, 0.127mmol) and DIEA (0.033mL, 0.190mmol).After room temperature keeps 5 hours, and adding 2-methyl-2H-tetrazolium-5-amine (25.1mg, 0.253mmol).Mixture was stirred 24 hours in the chamber, carry out purifying with MeOH (1mL) dilution and with reversed-phase HPLC, obtain embodiment 92, it is two-tfa salt (27mg, 55% yield). ¹H NMR (400MHz, δ ppm 1.08 (d, J=4.27Hz, 6H) 2.48 (s, 3H) 3.35-3.81 (m of chloroform-d), 8H) 4.29 (s, 3H) 4.59 (s, 1H) 7.13 (d, J=7.78Hz, 1H) 7.45-7.51 (m, 2H) 7.70-7.77 (m, 2H) 7.80-7.85 (m, 1H) 8.09 (d, 2H); MS (ES+) m/z:555 (M+H); LC retention time: 2.45 minutes (analytical HPLC method B).

Embodiment 93

N-(5-cyclopropyl-1,3,4-thiadiazoles-2-yl)-2-methyl-2-((5S)-2-methyl-8-(4-(morpholine-4-base carbonyl) phenyl)-5H-pyrido [3 ', 2 ': 5,6] pyrans is [2,3-b] pyridine-5-yl also) propionic acid amide

According to regard to the described condition of embodiment 14 steps 9, make the acid and the 2-amino-5-cyclopropyl thiadiazoles coupling that obtain by embodiment 92 steps 1, obtain embodiment 93. ¹H NMR (400MHz, δ ppm 1.16-1.41 (m, 10H) 2.27-2.38 (m, 1H) 2.57 (s, 3H) 3.43-3.93 (m of chloroform-d), 8H) 4.59 (s, 1H) 7.01 (d, J=7.78Hz, 1H) 7.51 (t, J=8.53Hz, 3H) 7.56-7.67 (m, 2H) 8.12 (d, 2H); MS (ES+) m/z:597 (M+H); LC retention time: 3.08 minutes (analytical HPLC method B).

Embodiment 94

4-((5S)-5-(1,1-dimethyl-2-((2-methyl-2H-tetrazolium-5-yl) amino)-2-oxoethyl)-8-methyl-5H-pyrido [3 ', 2 ': 5,6] pyrans is [2,3-b] pyridine-2-yl also)-N, the N-dimethyl benzamide

According to regard to the described condition of embodiment 92 steps 2, make the S-acid and 2-methyl-2H-tetrazolium-5-amine coupling that obtain by embodiment 10 steps 9, obtain embodiment 94. ¹H NMR (400MHz, δ ppm 1.21 (d, J=7.53Hz, 6H) 2.58 (s of chloroform-d), 3H) 3.05 (s, 3H) 3.19 (s, 3H) 4.38 (s, 3H) 4.68 (s, 1H) 7.03 (d, J=7.78Hz, 1H) 7.52 (d, J=8.28Hz, 2H) 7.58 (d, J=7.78Hz, 1H) 7.67 (d, J=7.78Hz, 1H) 7.74 (d, J=8.03Hz, 1H) 8.09 (d, J=8.28Hz, and 2H) 8.58 (s, 1H); MS (ES+) m/z:513 (M+H); LC retention time: 2.48 minutes (analytical HPLC method B).

The biologic activity data

Provided the AP-1 activity of embodiment (" Exp ") 1 to 94, wherein AP-1 EC ₅₀Less than 1 μ M.Also provided simultaneously the maximum inhibiting value of AP-1.As AP-1 EC ₅₀Provided glucocorticoid receptor (GR) binding affinity (Ki) greater than 1 μ M and/or maximum the inhibition less than 20% o'clock.The data that provide below obtain by the mensuration of mentioning in following table and describe in the application's said determination chapters and sections.

Claims

1. formula I compound or its enantiomer, diastereomer, tautomer or pharmacologically acceptable salt:

Wherein

Z is selected from heterocyclic radical, heteroaryl and cyano group;

J ₁Be chemical bond, O, S, SO, SO ₂, CH ₂Or CH ₂CH ₂With

J ₂And J ₃The chemical bond of respectively doing for oneself;

-OC (=O) R ₁₂,-NR ₁₂C (=O) R ₁₃,-NR ₁₂C (O) OR ₁₃,-NR ₁₂C (S) OR ₁₃,-S (O) _pR ₁₆, NR ₁₂SO ₂R ₁₆, dialkyl amido alkoxyl group, alkoxyalkyl oxygen base alkyl oxy, SO ₂NR ₁₂R ₁₃, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, heterocyclic radical, aryl and heteroaryl; And/or (ii) when feasible, R ₁, R ₂, R ₄, R ₅, R ₇And R ₈In each and be positioned at R on the adjacent atom ₁, R ₂, R ₄, R ₅, R ₇And R ₈In any form condensed ring with the atom that they connected;

P is 0,1 or 2.

2. compound or its enantiomer, diastereomer, tautomer or the pharmacologically acceptable salt of definition, wherein three loop sections as in claim 1

For

3. the compound or its enantiomer, diastereomer, tautomer or pharmacologically acceptable salt, the wherein R that define in each as in claim 1-2 ₄Be selected from alkyl sulfenyl, aryl, the aryl of replacement, cyano group, the CF of hydrogen, alkyl, thiazolinyl, alkyl sulfenyl, replacement ₃, alkoxyl group, halogen, hydroxyl, dialkyl amido, alkyl monosubstituted amino, dialkyl amido alkoxyl group, alkoxyl group alkoxyl group alkoxyl group and have one to three heteroatomic 4 to 7 yuan of heterocyclic radical that are selected from O, S and N.

4. the compound or its enantiomer, diastereomer, tautomer or pharmacologically acceptable salt, the wherein R that define in each as in claim 1-3 ₁, R ₂, R ₇And R ₈The hydrogen of respectively doing for oneself.

5. the compound or its enantiomer, diastereomer, tautomer or pharmacologically acceptable salt, the wherein R that define in each as in claim 1-4 ₅Be selected from hydrogen, haloalkyl, alkoxyl group, halogenated alkoxy, halogen, amino, dialkyl amido, heterocyclic radical, phenyl, halogenophenyl, alkyl (halo) _0-1Aryl, heterocyclic radical carbonyl (halo) _0-1Aryl, alkoxyl group (halo) _0-1Aryl, carboxyl (halo) _0-1Aryl, alkyl amino-carbonyl (halo) _0-1Aryl, dialkyl amino carbonyl (halo) _0-1Aryl, alkylamino, hydroxyl, dialkyl amido alkoxyl group, aryl-alkyl amino, alkoxy aryl alkylamino, alkyl heterocyclic, arylalkyl, heterocyclic radical alkoxyl group, aryl-heterocyclic base, arylalkyl (alkyl) amino, halogenated aryl, dialkyl amido (halo) _0-1Aryl, alkoxyl group alkoxyl group alkoxyl group, alkyl-carbonyl-amino, heteroaryl, dialkyl group (halo) _0-1Aryl, alkyl (halo) _0-1Aryl, hydroxyl (halo) _0-1Aryl, alkoxy carbonyl (halo) _0-1Aryl, alkyl-carbonyl-amino (halo) _0-1Aryl, dialkyl amino sulfonyl (halo) _0-1Aryl, alkyl sulfonyl-amino (halo) _0-1Aryl, alkyl sulfenyl (halo) _0-1Aryl, amino (halo) _0-1Aryl, alkyl-carbonyl aryl, alkyl-carbonyl (halo) aryl, aryloxy (halo) _0-1Aryl, alkyl sulphonyl aryl, alkyl sulphinyl aryl, mercapto oxygen Ji Fangji, cycloalkyloxy aryl, cycloalkyl amino carbonyl and cyano group (halo) _0-1Aryl.

6. the compound or its enantiomer, diastereomer, tautomer or the pharmacologically acceptable salt that define in each as in claim 1-5, wherein

R ₁₁Be hydrogen.

7. the compound or its enantiomer, diastereomer, tautomer or pharmacologically acceptable salt, the wherein R that define in each as in claim 1-6 ₉And R ₁₀Independently be selected from methyl separately, or R ₉And R ₁₀Form cyclopropyl, cyclobutyl or cyclopentyl with the carbon that they connected.

8. the compound or its enantiomer, diastereomer, tautomer or the pharmacologically acceptable salt that define in each as in claim 1-7, wherein

9. the compound or its enantiomer, diastereomer, tautomer or the pharmacologically acceptable salt that define in each as in claim 1-8, wherein

Z is

R ^mAnd R ⁿIdentical or different and when occurring, independently be selected from every turn hydrogen ,-CO _1-2R ^a,-C (O) NR ^aR ^b, C _1-6Alkyl ,-CF ₃,-CH ₂OH ,-SR ^c,-NR ^aR ^b,-CH ₂F, cyano group and C _3-6Cycloalkyl;

R ^oBe hydrogen or C _1-6Alkyl;

R ^aAnd R ^b(i) identical or different and when occurring, independently be selected from hydrogen, C at every turn _1-6The C of alkyl, replacement _1-6Alkyl, have heteroatomic 4 to 7 yuan of heterocyclic radicals and C that 1-3 is selected from O, S or N _3-6Cycloalkyl; Or (ii) R ^aWith R ^bForm together and have 1-3 heteroatomic 4 to the 7 yuan of heterocyclic radicals that are selected from O, S or N; With

R ^cBe selected from C _1-6Alkyl and C _3-6Cycloalkyl.

10. the compound or its enantiomer, diastereomer, tautomer or the pharmacologically acceptable salt that define in each as in claim 1-9, wherein

Z is

With

Cyclopropyl or

11. as the compound or its enantiomer, diastereomer, tautomer or the pharmacologically acceptable salt that in claim 1-10, define in each, described compound has following structure:

Wherein

R ₅For chlorine, dimethylamino,

X _aBe hydrogen or fluorine; With

X _bBe selected from (methyl) ₂NC (O)-, (ethyl) (methyl) NC (O)-,

With-C (O) N (methyl) (cyclopropyl).

12. formula I compound is selected from the disease of metabolic trouble and inflammatory diseases or Immunological diseases or the purposes in the obstacle in treatment, it comprises the compound with each chemical formula among the claim 1-11 of the patient treatment significant quantity that needs treatment.

13. according to the purposes of the compound of claim 12, wherein said disease or obstacle are selected from transplant rejection, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, asthma, inflammatory bowel, systemic lupus erythematous and psoriasis.

14. a pharmaceutical composition, it comprises according to each compound and pharmaceutically acceptable carrier among the claim 1-11.

15. drug regimen, it comprises according to each compound and immunosuppressor among the claim 1-11, carcinostatic agent, antiviral agent, anti-inflammatory agent, anti-mycotic agent, microbiotic, anti-angiogenic hyper-proliferative agent, antidepressive, the lipid depressant, lipid regulating agent, antidiabetic, antiobesity agent, hypotensive agent, anticoagulant and/or osteoporosis agent, wherein said antidiabetic is a biguanide compound, sulfonyl urea compound, glucosidase inhibitor, the PPAR gamma agonist, PPAR α/γ dual agonists, the SGLT2 inhibitor, the DP4 inhibitor, the aP2 inhibitor, euglycemic agent, glucagon-like peptide-1 (GLP-1), in Regular Insulin and/or the meglitinide a kind, 2 kinds, 3 kinds or more kinds of, wherein said antiobesity agent is a 'beta '3 adrenergic agonists, lipase inhibitor, thrombotonin (and Dopamine HCL) reuptake inhibitor, the thryoid receptor agonist, aP2 inhibitor and/or anoretic, wherein said lipid depressant is the MTP inhibitor, HMG CoA reductase inhibitor, inhibitor for squalene synthetic enzyme, fiber acid derivative, adjust on the ldl receptor activity, lipoxidase inhibitor or ACAT inhibitor, wherein said hypotensive agent are ACE inhibitor, angiotensin II receptor antagonists, the NEP/ACE inhibitor, calcium channel blocker and/or Beta-3 adrenergic blocker.